Folic acid ameliorates homocysteine-induced angiogenesis and portosystemic collaterals in cirrhotic rats

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"Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Division of Gastroenterology and Hepatology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Lin-Kuo Medical Center, Chang Gung University, College of Medicine, Taoyuan, Taiwan" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding authors at: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 112, Taiwan." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1392 "Ancho" => 2083 "Tamanyo" => 273077 ] ] "descripcion" => array:1 [ "en" => "Splanchnic hemodynamic parameters of cirrhotic rats with vehicle (V), homocysteine (H), homocysteine plus folic acid (H+F) or folic acid (F) administration. The number of each group was 8, 7, 5, 8, respectively. As compared with the vehicle group, homocysteine significantly increased SMA flow (P=0.046), which was tended to be reduced by folic acid. SMA: superior mesenteric artery; PV: portal vein." ] ] ] "textoCompleto" => "1IntroductionLiver cirrhosis with portal hypertension is characterized by increased intrahepatic resistance due to a distortion of intrahepatic vasculature caused by fibrosis, regeneration nodules and enhanced vasoconstrictive vascular tone <a class="elsevierStyleCrossRefs" href="#bib0190">[1–3]</a>. In contrast, the extrahepatic vascular beds, especially splanchnic and systemic vasculature, are vasodilated with splanchnic hyperemia and increased blood flow, leading to elevated portal inflow and pressure. Portosystemic collaterals then develop in order to divert the stagnant portal blood from the hypertensive portal system and such collaterals are prone to rupture with massive hemorrhage. Among them, gastroesophageal varices are the most notorious and the control of variceal bleeding significantly influences the prognosis of cirrhotic patients.Recent studies have reported that angiogenesis is involved in the development and maintenance of splanchnic hyperemia and portosystemic collaterals in cirrhosis and portal hypertension, and that vascular endothelial growth factor (VEGF) plays a prominent role in the process. In portal hypertensive rats, anti-VEGF receptor-2 (VEGFR-2) monoclonal antibody and the inhibitor of VEGFR-2 autophosphorylation have been shown to inhibit the formation of portosystemic collaterals and alleviated the severity of portal hypertension <a class="elsevierStyleCrossRef" href="#bib0205">[4]</a>.Homocysteine is formed during the metabolism of methionine, an essential amino acid derived from dietary protein <a class="elsevierStyleCrossRef" href="#bib0210">[5]</a>. Due to the adverse vascular effects <a class="elsevierStyleCrossRef" href="#bib0215">[6]</a>, hyperhomocysteinemia is a known risk factor for coronary heart disease and peripheral vascular diseases <a class="elsevierStyleCrossRef" href="#bib0220">[7]</a>. Surprisingly, the plasma homocysteine level has been shown to be higher in cirrhotic patients <a class="elsevierStyleCrossRef" href="#bib0225">[8]</a>, regardless of the etiology of cirrhosis <a class="elsevierStyleCrossRef" href="#bib0230">[9]</a>. An inverse correlation has also been reported between concentrations of homocysteine and folate <a class="elsevierStyleCrossRef" href="#bib0230">[9]</a>. Furthermore, a recent study reported an association between hyperhomocysteinemia and the severity of cirrhosis and that this exerted a negative impact after liver transplantation <a class="elsevierStyleCrossRef" href="#bib0235">[10]</a>.Several studies have investigated the vascular influences of homocysteine, including angiogenesis. However, these studies were not performed on cirrhotic subjects and the results are controversial: homocysteine has been reported to increase the synthesis of VEGF <a class="elsevierStyleCrossRefs" href="#bib0240">[11–13]</a>. On the contrary, some studies indicated that homocysteine impaired angiogenesis <a class="elsevierStyleCrossRefs" href="#bib0255">[14–16]</a>. Indeed, the relevant influences in cirrhosis deserve further investigation.Folic acid supplementation has been used to treat hyperhomocysteinemia and endothelial dysfunction <a class="elsevierStyleCrossRefs" href="#bib0270">[17,18]</a>. In patients with peripheral arterial disease and diabetes, the administration of folic acid and vitamins B1, B6, B12 have been shown to significantly reduce homocysteine levels and down-regulate VEGF expression in leukocytes <a class="elsevierStyleCrossRef" href="#bib0280">[19]</a>. In a human study, the plasma level of dimethylarginine, an endogenous inhibitor of NO, was shown to be positively correlated with plasma homocysteine and negatively correlated with folic acid levels <a class="elsevierStyleCrossRef" href="#bib0285">[20]</a>. Of note, plasma folate concentration have been shown to be lower in cirrhotic patients compared with controls <a class="elsevierStyleCrossRef" href="#bib0290">[21]</a>, in whom inadequate dietary intake and urinary folate loss are considered to be responsible for folate deficiency in patients with chronic liver disease <a class="elsevierStyleCrossRef" href="#bib0295">[22]</a>. Since previous studies have indicated higher homocysteine levels in cirrhotic patients, it would seem to be reasonable to give such patients a higher dose of folic acid to combat the adverse effects of homocysteine.Taken together, the current literature indicates the diverse actions of homocysteine on angiogenesis, the action of folate on homocysteine, and high homocysteine and low folate levels in cirrhotic patients. In addition, due to the lack of relevant studies on cirrhosis with portal hypertension, this study was designed to investigate the impacts of homocysteine and folic acid treatment on mesenteric angiogenesis and severity of portosystemic collaterals in rats with common bile duct ligation (CBDL)-induced chronic liver injury.2Material and methods2.1Animal modelMale Sprague-Dawley rats weighing 240–270g at the time of surgery were used. Secondary biliary cirrhosis was induced 4 weeks after common bile duct ligation (CBDL) as previously described <a class="elsevierStyleCrossRef" href="#bib0300">[23]</a>. Animals were allowed an acclimatization period for 1 week at the Animal Center of Department of Medical Research, Taipei Veterans General Hospital. Rats were housed at constant temperature (25±2°C), humidity (60±10%) and a light/dark (12/12h) cycle. Access to food and water throughout the experimental period was allowed ad libitum. This study was approved by Taipei Veterans General Hospital Animal Committee (grant numbers: IACUC2013-151, IACUC2013-191, and IACUC2013-194). All animals received humane care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” published by the National Institutes of Health, the United States (NIH publication 86-23, revised 1985).2.2Measurement of systemic and portal hemodynamicsMean arterial pressure (MAP), heart rate (HR) and portal pressure (PP) were measured by catheterization of the right femoral artery and ileocolic vein respectively, which were connected to Spectramed DTX transducer (Spectramed Inc., Oxnard, CA, U.S.A.). MAP, HR and PP were continuously recorded on a multi-channel recorder (model RS 3400, Gould Inc., Cupertino, CA, U.S.A.).Superior mesenteric artery (SMA) flow and portal vein (PV) flow were measured by a pulsed-Doppler flow transducer (T206 small animal blood flow meter, Transonic System Inc., Ithaca, NY, U.S.A.). Cardiac output (CO) was measured by thermodilution, as previously described <a class="elsevierStyleCrossRef" href="#bib0305">[24]</a>. Cardiac index (CI, ml/min/100g body weight (BW)) was calculated as CO per 100g BW. Stoke volume (SV) was calculated as CO divided by HR (ml/beats). Systemic vascular resistance (SVR, mmHg/ml/min/100g BW) was calculated as MAP divided by CI, and SMA resistance (mmHg/ml/min/100g BW) was calculated as (MAP-PP)/SMA flow per 100g BW.2.3Portosystemic shunting analysisPortosystemic shunting was determined as previously described, substituting color for radioactive microspheres <a class="elsevierStyleCrossRef" href="#bib0310">[25]</a>. Portal-systemic shunting was calculated as lung/(liver+lung) microspheres. Color microspheres have been shown to provide similar results to radioactive microspheres <a class="elsevierStyleCrossRef" href="#bib0315">[26]</a>.2.4Immunofluorescent study for mesenteric vascular densityMesenteric angiogenesis was quantified using CD31-labeled microvascular networks in rat mesenteric connective tissue windows according to previous studies <a class="elsevierStyleCrossRefs" href="#bib0310">[25], [27]</a>.2.5Western analysisProtein expressions were analyzed by Western blotting as previously described <a class="elsevierStyleCrossRef" href="#bib0325">[28]</a>. Blots were incubated with the primary antibodies [inducible NO synthase (iNOS), endothelial NO synthase (eNOS), phospho-eNOS (p-eNOS), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), platelet-derived growth factor receptor β (PDGFRβ): Cell Signaling Technology, Beverly, MA, U.S.A.; VEGF, phospho-VEGFR-2 (p-VEGFR2), platelet-derived growth factor (PDGF): Santa Cruz Biotechnology, Santa Cruz, CA, U.S.A.]. The blots were then incubated with the appropriate secondary antibodies (peroxidase-labeled anti-rabbit IgG or anti-mouse IgG, Cell Signaling Technology). The specific proteins were detected by enhanced chemiluminescence (Immobilon Western Chemiluminescent HRP Substrate, Merk Millipore Co., Billerica, MA, U.S.A.). With a computer assisted video densitometer and digitalized system (BioSpectrum® 600 Imaging System, Ultra-Violet Products Ltd., Upland, CA, U.S.A.), the blots were scanned, photographed and then the signal intensity (integral volume) of the appropriate band was analyzed.2.6Measurement of biochemical parameters of liver and renal injuryAlanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, blood urea nitrogen (BUN), and creatinine levels were measured with a Cobas Mira analyzer (GMI Inc., Ramsey, MN, U.S.A.).2.7Drugsdl-Homocysteine thiolactone and folic acid were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO, U.S.A.).2.8Data analysisAll results are expressed as mean±S.D. Statistical analyses were performed using an unpaired Student's t-test or ANOVA with LSD test as appropriate. Results are considered statistically significant at a two-tailed P-value less than 0.05. SPSS version 21 statistical software package for Windows (SPSS Inc., Chicago, IL, USA) was used for all analyses.2.9Study protocolCommon bile duct ligation was performed in male Sprague-Dawley rats. CBDL rats developed significant liver fibrosis 2 weeks after CBDL and liver cirrhosis 4 weeks after CBDL <a class="elsevierStyleCrossRef" href="#bib0300">[23]</a>. CBDL rats were subdivided to receive the following treatments since the 14th to 28th day after surgery: (1) vehicle (V group); (2) dl-homocysteine thiolactone (1g/kg/day, oral gavage, H group); (3) dl-homocysteine thiolactone with folic acid (100mg/kg/day according to a previous study <a class="elsevierStyleCrossRef" href="#bib0330">[29]</a>, oral gavage, H+F group); (4) folic acid (F group). On the 29th day after CBDL, two series of experiments using four independent treatment groups for each series were performed: first series (n=10 for each group at the time of CBDL): measurement of the severity of portosystemic shunting using color microsphere method; second series (n=10 for each group at the time of CBDL): (a) BW and hemodynamic measurements including: MAP, HR, PP, CO, CI, SV, SVR, SMA flow, PV flow; (b) measurements of plasma levels of ALT, AST, total bilirubin, BUN, and creatinine; (c) mesenteric protein expressions of VEGF, VEGFR2, p-VEGFR2, PDGF, PDGFR-β, eNOS, p-eNOS, iNOS, COX-1, COX-2 with Western blot analysis; (d) mesenteric vascular density assessment with immunofluorescence.3Results3.1HemodynamicsHomocysteine significantly reduced the BW (g) as compared with the vehicle (control) group [vehicle (V, n=8) vs. homocysteine (H, n=7) vs. homocysteine plus folic acid (H+F, n=5) vs. folic acid (F, n=8)]: 395.0±36.1 vs. 338.6±23.4 vs. 367.6±29.6 vs. 369.6±34.7; V vs. H, P=0.001.<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the systemic hemodynamic data of the study groups after the received treatment. Folate significantly elevated MAP and HR. The MAP values (mmHg) after each different treatment were 89.9±9.4 (V) vs. 83.4±4.8 (H) vs. 95.8±5.7 (H+F) vs. 103.2±9.2 (F) (V vs. F, P=0.005; H vs. H+F, P=0.012; and H vs. F, P<0.001). While HR values (bpm) were 232.3±33.3 (V) vs. 233.7±47.2 (H) vs. 293.8±44.4 (H+F) vs. 303.3±55.5 (F) (V vs. H+F, P=0.027; V vs. F, P=0.005; and H vs. F, P=0.004). There were no significant differences in other hemodynamic parameters among the groups, including CO, CI, SV, and SVR (all P>0.05 among groups).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> shows the splanchnic hemodynamic data of the study groups after the received treatment. There was no significant difference of PP, PV flow and SMA resistance among groups (P>0.05) except that homocysteine increased SMA flow (ml/min/100g) as compared with vehicle, which was tended to be reduced by folic acid [6.7±0.2 (V) vs. 9.5±1.6 (H) vs. 8.8±2.1 (H+F) vs. 8.3±2.6 (F); V vs. H, P=0.046].<elsevierMultimedia ident="fig0010"></elsevierMultimedia>3.2Liver and renal biochemistry parameters<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> shows the liver and renal biochemistry data [V (n=8) vs. H (n=7) vs. H+F (n=5) vs. F (n=8)]. Folic acid did not significantly influence ALT, AST or Cr levels but it decreased BUN and total bilirubin levels as compared with the vehicle and homocysteine groups: BUN (mg/dL): 24.3±3.8 vs. 23.3±3.6 vs. 20.7±2.3 vs. 20.7±3.9, V vs. F, P=0.046; total bilirubin (mg/dL): 7.31±1.00 vs. 8.39±1.45 vs. 8.06±0.56 vs. 6.33±2.92, H vs. F, P=0.011.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>3.3Shunting and mesenteric window vascular area<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a> depicts the shunting [V (n=10) vs. H (n=8) vs. H+F (n=6) vs. F (n=8)] and mesenteric window vascular area ratio [V (n=8) vs. H (n=7) vs. H+F (n=5) vs. F (n=8)]. Homocysteine significantly increased the shunting ratio (%) [62.06±20.37 (V) vs. 81.49±14.58 (H) vs. 40.51±12.79 (H+F) vs. 32.80±19.68 (F); V vs. H, P=0.038; V vs. H+F, P=0.029; V vs. F, P=0.002; H vs. H+F, P<0.001; and H vs. F, P<0.001], which was reduced by folic acid. The mesenteric vascular density (vascular area/mesenteric window area (%): 7.81±3.09 vs. 11.73±4.27 vs. 5.35±3.58 vs. 7.12±4.02, H vs. V, P=0.031; H vs. H+F, P=0.005; H vs. F, P=0.027) also exhibited the same statistical trend.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>3.4Mesenteric proangiogenic factor protein expressions<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a> discloses the protein expressions of mesenteric proangiogenic factors [V (n=8) vs. H (n=7) vs. H+F (n=5) vs. F (n=8)]. There were no significant differences of VEGFR-2, p-VEGFR2 and COX2 expressions. Homocysteine significantly up-regulated VEGF and p-eNOS expressions, which were down-regulated by folic acid [VEGF (/β-actin): 1.12±0.51 (V) vs. 2.19±1.67 (H) vs. 0.93±0.40 (H+F) vs. 0.86±0.44 (F), V vs. H, P=0.026; H vs. H+F, P=0.037; H vs. F, P=0.010; p-eNOS: 1.82±0.41 vs. 3.00±0.83 vs. 1.16±0.48 vs. 1.49±0.71, V vs. H, P=0.005; H vs. H+F, P<0.001; H vs. F, P<0.001]. Homocysteine up-regulated eNOS expression as compared with vehicle [eNOS: 0.45±0.16 vs. 0.93±0.38 vs. 0.79±0.63 vs. 0.68±0.28, V vs. H, P=0.030]. There were no significant differences in COX1 expressions among the study groups [COX1: 2.03±1.38 vs. 1.37±0.71 vs. 0.94±0.19 vs. 1.09±0.78, V vs. H+F, P=0.050]. Homocysteine tended to increase the p-VEGFR2/VEGFR2, which was tended to be reduced by folate (P>0.05).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>4DiscussionHyperdynamic circulatory status is characterized by systemic hypotension and extrahepatic vasodilatation. Compatible with our previous study <a class="elsevierStyleCrossRef" href="#bib0335">[30]</a>, homocysteine did not affect MAP and HR in cirrhotic rats in this study. However, the addition of folic acid to homocysteine and the single administration of folic acid significantly increased MAP and HR in cirrhotic rats. MAP is positively correlated with HR and SV. Since the SV was not influenced by folate, the elevation of MAP might be related to an increase in HR. Although it has been reported that in male smokers, moderate amount of folic acid and vitamins supplement increased the vagal control of HR (+23%; P<0.05) <a class="elsevierStyleCrossRef" href="#bib0340">[31]</a>, interpolating results from different study designs should be made with caution. Based on the currently available results, we could only note that the hemodynamic influence of folic acid in cirrhotic subjects with portal hypertension has not been reported previously and our finding suggests that folic acid may be able to reverse the profound systemic hypotension in portal hypertension with hyperdynamic circulation. Furthermore, the homocysteine-induced elevation of SMA flow tended to be reduced by folic acid. The reduction of blood flow in splanchnic vascular bed may lessen the drive to develop portosystemic collaterals.The influences of homocysteine on angiogenesis have been debated. For instance, it has been found that in homocysteine-treated cultured cells, there was a 1.3-fold increased secretion of VEGF <a class="elsevierStyleCrossRef" href="#bib0240">[11]</a>. Another study showed that homocysteine up-regulated VEGF mRNA expression in a dose- and time-dependent manner in macrophages, followed by increased VEGF secretion <a class="elsevierStyleCrossRef" href="#bib0245">[12]</a>. Hyperhomocysteinemia also increased VEGF expression in rat retina <a class="elsevierStyleCrossRef" href="#bib0250">[13]</a>. In contrast, Nagai et al. found that the plasma concentration of homocysteine was inversely correlated with the development of collateral circulation in patients with coronary artery disease <a class="elsevierStyleCrossRef" href="#bib0255">[14]</a>. Moreover, hyperhomocysteinemia impaired ischemia-induced angiogenesis and collateral vascular formation in a rat model with hindlimb ischemia, and that this may have been mediated by reduced NO bioavailability in a hyperhomocysteinemic state <a class="elsevierStyleCrossRef" href="#bib0260">[15]</a>. A recent study also demonstrated that homocysteine induced growth arrest in human endothelial cells <a class="elsevierStyleCrossRef" href="#bib0265">[16]</a>. The differences in these results may be related to the differences in study design with various diseases models and subjects.Interestingly, the current study found that the shunting degree, which represents the severity of collaterals, was significantly reduced by folic acid in cirrhotic rats, with or without hyperhomocysteinemia. In addition, the mesenteric vascular density and VEGF expression were also down-regulated. Therefore, folic acid reduced shunting in two steps: first, by decreasing splanchnic blood flow and mitigating the stress to form portosystemic collaterals; second, by reducing splanchnic angiogenesis related to VEGF down-regulation. In addition, the mesenteric protein expression of p-eNOS, representing eNOS activation, was also upregulated by homocysteine and reversed by folate. Interestingly, it has been demonstrated in cultured endothelial cells that folic acid activated eNOS via the modulation of eNOS phosphorylation <a class="elsevierStyleCrossRef" href="#bib0345">[32]</a>. Furthermore, eNOS is the downstream effector of VEGF in angiogenesis <a class="elsevierStyleCrossRef" href="#bib0350">[33]</a>. Although previous studies have suggested the anti-angiogenesis effect of homocysteine <a class="elsevierStyleCrossRefs" href="#bib0260">[15,16]</a>, the homocysteine concentrations were 0.2–5mmol/L, much higher than those in patients with hyperhomocysteinemia. Our previous investigation also revealed that in cirrhotic rats with homocysteinemia, the plasma concentration was 18.4±0.9μM <a class="elsevierStyleCrossRef" href="#bib0335">[30]</a>, much lower than those of the aforementioned studies <a class="elsevierStyleCrossRefs" href="#bib0260">[15,16]</a>. More portosystemic collaterals were also noted as compared with the vehicle-administered to cirrhotic rats <a class="elsevierStyleCrossRef" href="#bib0335">[30]</a>, supporting the angiogenesis effect of homocysteine in this disease entity. Therefore, folic acid may overcome homocysteine-induced pathological angiogenesis in cirrhosis via down-regulating VEGF-eNOS signaling pathway. Of note, the techniques used to survey the tissue derangements caused by cirrhosis in animal studies are usually invasive and harmful, such as the microsphere method to determine shunting and CD31 immunofluorescent staining for mesenteric angiogenesis. Such methods are not readily applied to patients because of the associated organ damages. Hence, non-invasive modalities have been developed, such as the diffusion-weighted MR imaging, for the prediction of esophageal varices and liver fibrosis <a class="elsevierStyleCrossRefs" href="#bib0355">[34–37]</a> and they are believed to be promising tools for clinical investigations and applications.Folic acid also significantly reduced total bilirubin level in cirrhotic rats. Since bilirubin is a surrogate marker of liver function, the finding provides the beneficial evidence of folic acid use in cirrhosis. To sum up, folic acid reversed homocysteine-induced systemic hypotension in cirrhotic rats. The severity of shunting and mesenteric angiogenesis were also mitigated, which may be related to VEGF-eNOS pathway downregulation. Folic acid may be a feasible candidate to alleviate portosystemic collaterals in cirrhosis. Nevertheless, further clinical investigation is required.AbbreviationsALTalanine aminotransferaseASTaspartate aminotransferaseBUNblood urea nitrogenBWbody weightCBDLcommon bile duct ligationCD31cluster of differentiation 31CIcardiac indexCOcardiac outputCOXcyclooxygenaseeNOSendothelial NO synthaseF groupfolic acid-treated groupH groupdl-homocysteine thiolactone-treated groupH+F groupdl-homocysteine thiolactone with folic acid-treated groupHRheart rateMAPmean arterial pressurePDGFRβplatelet-derived growth factor receptor βp-eNOSphosphorylated-endothelial nitric oxide synthasePPportal pressurePVportal veinSMAsuperior mesenteric arterySVstoke volumeSVRsystemic vascular resistanceVEGFvascular endothelial growth factorVEGFR-2VEGF receptor-2V groupvehicle-treated groupConflict of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1233321" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1145653" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Animal model" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Measurement of systemic and portal hemodynamics" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Portosystemic shunting analysis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Immunofluorescent study for mesenteric vascular density" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Western analysis" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Measurement of biochemical parameters of liver and renal injury" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Drugs" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Data analysis" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Study protocol" ] ] ] 4 => array:3 [ "identificador" => "sec0060" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Hemodynamics" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Liver and renal biochemistry parameters" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Shunting and mesenteric window vascular area" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Mesenteric proangiogenic factor protein expressions" ] ] ] 5 => array:2 [ "identificador" => "sec0085" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 7 => array:2 [ "identificador" => "xack422294" "titulo" => "Acknowledgements" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-05-17" "fechaAceptado" => "2018-11-23" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1145653" "palabras" => array:5 [ 0 => "Homocysteine" 1 => "Folic acid" 2 => "Angiogenesis" 3 => "Liver cirrhosis" 4 => "Portosystemic collaterals" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and ObjectivesLiver cirrhosis is characterized by increased intrahepatic resistance, splanchnic vasodilation/angiogenesis, and formation of portosystemic collateral vessels. Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage. Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients. It is also known that folic acid supplementation reverses the effects of homocysteine. However, the treatment effect in cirrhosis has yet to be investigated. Material and methodsLiver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (CBDL). The CBDL rats randomly received (1) vehicle; (2) dl-homocysteine thiolactone (1g/kg/day); (3) dl-homocysteine thiolactone plus folic acid (100mg/kg/day); or (4) folic acid. On the 29th day, hemodynamic parameters, liver and renal biochemistry, protein expressions of proangiogenic factors, mesenteric vascular density and portosystemic shunting were evaluated. ResultsIn the cirrhotic rats, homocysteine increased mesenteric vascular density and the severity of shunting. It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor (VEGF) and phosphorylated-endothelial nitric oxide synthase (p-eNOS). These effects were reversed by folic acid treatment (P<0.05). ConclusionFolic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats, which may be related to down-regulation of the VEGF-NO signaling pathway." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1432 "Ancho" => 3167 "Tamanyo" => 433606 ] ] "descripcion" => array:1 [ "en" => "Systemic hemodynamic parameters of cirrhotic rats with vehicle (V), homocysteine (H), homocysteine plus folic acid (H+F) or folic acid (F) administration. The number of each group was 8, 7, 5, 8, respectively. SVR: systemic vascular resistance. Folic acid significantly increased mean arterial pressure and heart rate as compared with the vehicle and homocysteine (P<0.05)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1392 "Ancho" => 2083 "Tamanyo" => 273077 ] ] "descripcion" => array:1 [ "en" => "Splanchnic hemodynamic parameters of cirrhotic rats with vehicle (V), homocysteine (H), homocysteine plus folic acid (H+F) or folic acid (F) administration. The number of each group was 8, 7, 5, 8, respectively. As compared with the vehicle group, homocysteine significantly increased SMA flow (P=0.046), which was tended to be reduced by folic acid. SMA: superior mesenteric artery; PV: portal vein." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1412 "Ancho" => 3167 "Tamanyo" => 292197 ] ] "descripcion" => array:1 [ "en" => "Plasma levels of liver and renal biochemistry in cirrhotic rats with vehicle (V), homocysteine (H), homocysteine plus folic acid (H+F) or folic acid (F) administration. The number of each group was 8, 7, 5, 8, respectively. Folic acid significantly reduced the BUN and total bilirubin levels (P<0.05). ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 676 "Ancho" => 2333 "Tamanyo" => 167689 ] ] "descripcion" => array:1 [ "en" => "Shunting ratio and mesenteric vascular density in cirrhotic rats with vehicle (V), homocysteine (H), homocysteine plus folic acid (H+F) or folic acid (F) administration. The number of each group was 10, 8, 6, 8 for shunting study and 8, 7, 5, 8 for vascular density study, respectively. As compared with vehicle, homocysteine significant increased shunting ratio and vascular area per unit area of mesenteric window (P<0.05), which were reversed by folic acid (P<0.05)." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 3054 "Ancho" => 3167 "Tamanyo" => 523536 ] ] "descripcion" => array:1 [ "en" => "Mesenteric proangiogenic factors protein expressions in cirrhotic rats with vehicle (V), homocysteine (H), homocysteine plus folic acid (H+F) or folic acid (F) administration. The number of each group was 8, 7, 5, 8, respectively. 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Original article

Hsin-Ling Hoa,b,c, Ming-Hung Tsaid, Yu-Hsin Hsiehe, Teh-Ia Huob,e, Ching-Chih Changa,f, Fa-Yauh Leea,e,

Corresponding author

fylee@vghtpe.gov.tw

Corresponding authors at: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 112, Taiwan.

, Hui-Chun Huanga,e,f,

Corresponding author

hchuang2@vghtpe.gov.tw

Corresponding authors at: Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shi-Pai Road, Taipei 112, Taiwan.

, Ming-Chih Houa,e, Shou-Dong Leea,g

a Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan

b Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan

c Division of Gastroenterology and Hepatology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan

d Division of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Lin-Kuo Medical Center, Chang Gung University, College of Medicine, Taoyuan, Taiwan

e Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

f Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

g Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan

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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Splanchnic hemodynamic parameters of cirrhotic rats with vehicle &#40;V&#41;&#44; homocysteine &#40;H&#41;&#44; homocysteine plus folic acid &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; or folic acid &#40;F&#41; administration&#46; The number of each group was 8&#44; 7&#44; 5&#44; 8&#44; respectively&#46; As compared with the vehicle group&#44; homocysteine significantly increased SMA flow &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;046&#41;&#44; which was tended to be reduced by folic acid&#46; SMA&#58; superior mesenteric artery&#59; PV&#58; portal vein&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Liver cirrhosis with portal hypertension is characterized by increased intrahepatic resistance due to a distortion of intrahepatic vasculature caused by fibrosis&#44; regeneration nodules and enhanced vasoconstrictive vascular tone <a class="elsevierStyleCrossRefs" href="#bib0190">&#91;1&#8211;3&#93;</a>&#46; In contrast&#44; the extrahepatic vascular beds&#44; especially splanchnic and systemic vasculature&#44; are vasodilated with splanchnic hyperemia and increased blood flow&#44; leading to elevated portal inflow and pressure&#46; Portosystemic collaterals then develop in order to divert the stagnant portal blood from the hypertensive portal system and such collaterals are prone to rupture with massive hemorrhage&#46; Among them&#44; gastroesophageal varices are the most notorious and the control of variceal bleeding significantly influences the prognosis of cirrhotic patients&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Recent studies have reported that angiogenesis is involved in the development and maintenance of splanchnic hyperemia and portosystemic collaterals in cirrhosis and portal hypertension&#44; and that vascular endothelial growth factor &#40;VEGF&#41; plays a prominent role in the process&#46; In portal hypertensive rats&#44; anti-VEGF receptor-2 &#40;VEGFR-2&#41; monoclonal antibody and the inhibitor of VEGFR-2 autophosphorylation have been shown to inhibit the formation of portosystemic collaterals and alleviated the severity of portal hypertension <a class="elsevierStyleCrossRef" href="#bib0205">&#91;4&#93;</a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Homocysteine is formed during the metabolism of methionine&#44; an essential amino acid derived from dietary protein <a class="elsevierStyleCrossRef" href="#bib0210">&#91;5&#93;</a>&#46; Due to the adverse vascular effects <a class="elsevierStyleCrossRef" href="#bib0215">&#91;6&#93;</a>&#44; hyperhomocysteinemia is a known risk factor for coronary heart disease and peripheral vascular diseases <a class="elsevierStyleCrossRef" href="#bib0220">&#91;7&#93;</a>&#46; Surprisingly&#44; the plasma homocysteine level has been shown to be higher in cirrhotic patients <a class="elsevierStyleCrossRef" href="#bib0225">&#91;8&#93;</a>&#44; regardless of the etiology of cirrhosis <a class="elsevierStyleCrossRef" href="#bib0230">&#91;9&#93;</a>&#46; An inverse correlation has also been reported between concentrations of homocysteine and folate <a class="elsevierStyleCrossRef" href="#bib0230">&#91;9&#93;</a>&#46; Furthermore&#44; a recent study reported an association between hyperhomocysteinemia and the severity of cirrhosis and that this exerted a negative impact after liver transplantation <a class="elsevierStyleCrossRef" href="#bib0235">&#91;10&#93;</a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Several studies have investigated the vascular influences of homocysteine&#44; including angiogenesis&#46; However&#44; these studies were not performed on cirrhotic subjects and the results are controversial&#58; homocysteine has been reported to increase the synthesis of VEGF <a class="elsevierStyleCrossRefs" href="#bib0240">&#91;11&#8211;13&#93;</a>&#46; On the contrary&#44; some studies indicated that homocysteine impaired angiogenesis <a class="elsevierStyleCrossRefs" href="#bib0255">&#91;14&#8211;16&#93;</a>&#46; Indeed&#44; the relevant influences in cirrhosis deserve further investigation&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Folic acid supplementation has been used to treat hyperhomocysteinemia and endothelial dysfunction <a class="elsevierStyleCrossRefs" href="#bib0270">&#91;17&#44;18&#93;</a>&#46; In patients with peripheral arterial disease and diabetes&#44; the administration of folic acid and vitamins B1&#44; B6&#44; B12 have been shown to significantly reduce homocysteine levels and down-regulate VEGF expression in leukocytes <a class="elsevierStyleCrossRef" href="#bib0280">&#91;19&#93;</a>&#46; In a human study&#44; the plasma level of dimethylarginine&#44; an endogenous inhibitor of NO&#44; was shown to be positively correlated with plasma homocysteine and negatively correlated with folic acid levels <a class="elsevierStyleCrossRef" href="#bib0285">&#91;20&#93;</a>&#46; Of note&#44; plasma folate concentration have been shown to be lower in cirrhotic patients compared with controls <a class="elsevierStyleCrossRef" href="#bib0290">&#91;21&#93;</a>&#44; in whom inadequate dietary intake and urinary folate loss are considered to be responsible for folate deficiency in patients with chronic liver disease <a class="elsevierStyleCrossRef" href="#bib0295">&#91;22&#93;</a>&#46; Since previous studies have indicated higher homocysteine levels in cirrhotic patients&#44; it would seem to be reasonable to give such patients a higher dose of folic acid to combat the adverse effects of homocysteine&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Taken together&#44; the current literature indicates the diverse actions of homocysteine on angiogenesis&#44; the action of folate on homocysteine&#44; and high homocysteine and low folate levels in cirrhotic patients&#46; In addition&#44; due to the lack of relevant studies on cirrhosis with portal hypertension&#44; this study was designed to investigate the impacts of homocysteine and folic acid treatment on mesenteric angiogenesis and severity of portosystemic collaterals in rats with common bile duct ligation &#40;CBDL&#41;-induced chronic liver injury&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0040">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0045">Animal model</span><p id="par0035" class="elsevierStylePara elsevierViewall">Male Sprague-Dawley rats weighing 240&#8211;270<span class="elsevierStyleHsp" style=""></span>g at the time of surgery were used&#46; Secondary biliary cirrhosis was induced 4 weeks after common bile duct ligation &#40;CBDL&#41; as previously described <a class="elsevierStyleCrossRef" href="#bib0300">&#91;23&#93;</a>&#46; Animals were allowed an acclimatization period for 1 week at the Animal Center of Department of Medical Research&#44; Taipei Veterans General Hospital&#46; Rats were housed at constant temperature &#40;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#44; humidity &#40;60<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#37;&#41; and a light&#47;dark &#40;12&#47;12<span class="elsevierStyleHsp" style=""></span>h&#41; cycle&#46; Access to food and water throughout the experimental period was allowed ad libitum&#46; This study was approved by Taipei Veterans General Hospital Animal Committee &#40;grant numbers&#58; IACUC2013-151&#44; IACUC2013-191&#44; and IACUC2013-194&#41;&#46; All animals received humane care according to the criteria outlined in the &#8220;Guide for the Care and Use of Laboratory Animals&#8221; published by the National Institutes of Health&#44; the United States &#40;NIH publication 86-23&#44; revised 1985&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0050">Measurement of systemic and portal hemodynamics</span><p id="par0040" class="elsevierStylePara elsevierViewall">Mean arterial pressure &#40;MAP&#41;&#44; heart rate &#40;HR&#41; and portal pressure &#40;PP&#41; were measured by catheterization of the right femoral artery and ileocolic vein respectively&#44; which were connected to Spectramed DTX transducer &#40;Spectramed Inc&#46;&#44; Oxnard&#44; CA&#44; U&#46;S&#46;A&#46;&#41;&#46; MAP&#44; HR and PP were continuously recorded on a multi-channel recorder &#40;model RS 3400&#44; Gould Inc&#46;&#44; Cupertino&#44; CA&#44; U&#46;S&#46;A&#46;&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Superior mesenteric artery &#40;SMA&#41; flow and portal vein &#40;PV&#41; flow were measured by a pulsed-Doppler flow transducer &#40;T206 small animal blood flow meter&#44; Transonic System Inc&#46;&#44; Ithaca&#44; NY&#44; U&#46;S&#46;A&#46;&#41;&#46; Cardiac output &#40;CO&#41; was measured by thermodilution&#44; as previously described <a class="elsevierStyleCrossRef" href="#bib0305">&#91;24&#93;</a>&#46; Cardiac index &#40;CI&#44; ml&#47;min&#47;100<span class="elsevierStyleHsp" style=""></span>g body weight &#40;BW&#41;&#41; was calculated as CO per 100<span class="elsevierStyleHsp" style=""></span>g BW&#46; Stoke volume &#40;SV&#41; was calculated as CO divided by HR &#40;ml&#47;beats&#41;&#46; Systemic vascular resistance &#40;SVR&#44; mmHg&#47;ml&#47;min&#47;100<span class="elsevierStyleHsp" style=""></span>g BW&#41; was calculated as MAP divided by CI&#44; and SMA resistance &#40;mmHg&#47;ml&#47;min&#47;100<span class="elsevierStyleHsp" style=""></span>g BW&#41; was calculated as &#40;MAP-PP&#41;&#47;SMA flow per 100<span class="elsevierStyleHsp" style=""></span>g BW&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0055">Portosystemic shunting analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Portosystemic shunting was determined as previously described&#44; substituting color for radioactive microspheres <a class="elsevierStyleCrossRef" href="#bib0310">&#91;25&#93;</a>&#46; Portal-systemic shunting was calculated as lung&#47;&#40;liver<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>lung&#41; microspheres&#46; Color microspheres have been shown to provide similar results to radioactive microspheres <a class="elsevierStyleCrossRef" href="#bib0315">&#91;26&#93;</a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0060">Immunofluorescent study for mesenteric vascular density</span><p id="par0055" class="elsevierStylePara elsevierViewall">Mesenteric angiogenesis was quantified using CD31-labeled microvascular networks in rat mesenteric connective tissue windows according to previous studies <a class="elsevierStyleCrossRefs" href="#bib0310">&#91;25&#93;&#44; &#91;27&#93;</a>&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0065">Western analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Protein expressions were analyzed by Western blotting as previously described <a class="elsevierStyleCrossRef" href="#bib0325">&#91;28&#93;</a>&#46; Blots were incubated with the primary antibodies &#91;inducible NO synthase &#40;iNOS&#41;&#44; endothelial NO synthase &#40;eNOS&#41;&#44; phospho-eNOS &#40;p-eNOS&#41;&#44; cyclooxygenase-1 &#40;COX-1&#41;&#44; cyclooxygenase-2 &#40;COX-2&#41;&#44; platelet-derived growth factor receptor &#946; &#40;PDGFR&#946;&#41;&#58; Cell Signaling Technology&#44; Beverly&#44; MA&#44; U&#46;S&#46;A&#46;&#59; VEGF&#44; phospho-VEGFR-2 &#40;p-VEGFR2&#41;&#44; platelet-derived growth factor &#40;PDGF&#41;&#58; Santa Cruz Biotechnology&#44; Santa Cruz&#44; CA&#44; U&#46;S&#46;A&#46;&#93;&#46; The blots were then incubated with the appropriate secondary antibodies &#40;peroxidase-labeled anti-rabbit IgG or anti-mouse IgG&#44; Cell Signaling Technology&#41;&#46; The specific proteins were detected by enhanced chemiluminescence &#40;Immobilon Western Chemiluminescent HRP Substrate&#44; Merk Millipore Co&#46;&#44; Billerica&#44; MA&#44; U&#46;S&#46;A&#46;&#41;&#46; With a computer assisted video densitometer and digitalized system &#40;BioSpectrum<span class="elsevierStyleSup">&#174;</span> 600 Imaging System&#44; Ultra-Violet Products Ltd&#46;&#44; Upland&#44; CA&#44; U&#46;S&#46;A&#46;&#41;&#44; the blots were scanned&#44; photographed and then the signal intensity &#40;integral volume&#41; of the appropriate band was analyzed&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0070">Measurement of biochemical parameters of liver and renal injury</span><p id="par0065" class="elsevierStylePara elsevierViewall">Alanine aminotransferase &#40;ALT&#41;&#44; aspartate aminotransferase &#40;AST&#41;&#44; total bilirubin&#44; blood urea nitrogen &#40;BUN&#41;&#44; and creatinine levels were measured with a Cobas Mira analyzer &#40;GMI Inc&#46;&#44; Ramsey&#44; MN&#44; U&#46;S&#46;A&#46;&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0075">Drugs</span><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSmallCaps">dl</span>-Homocysteine thiolactone and folic acid were purchased from Sigma-Aldrich Chemical Co&#46; &#40;St&#46; Louis&#44; MO&#44; U&#46;S&#46;A&#46;&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;8</span><span class="elsevierStyleSectionTitle" id="sect0080">Data analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">All results are expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>S&#46;D&#46; Statistical analyses were performed using an unpaired Student&#39;s <span class="elsevierStyleItalic">t</span>-test or ANOVA with LSD test as appropriate&#46; Results are considered statistically significant at a two-tailed <span class="elsevierStyleItalic">P</span>-value less than 0&#46;05&#46; SPSS version 21 statistical software package for Windows &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41; was used for all analyses&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;9</span><span class="elsevierStyleSectionTitle" id="sect0085">Study protocol</span><p id="par0080" class="elsevierStylePara elsevierViewall">Common bile duct ligation was performed in male Sprague-Dawley rats&#46; CBDL rats developed significant liver fibrosis 2 weeks after CBDL and liver cirrhosis 4 weeks after CBDL <a class="elsevierStyleCrossRef" href="#bib0300">&#91;23&#93;</a>&#46; CBDL rats were subdivided to receive the following treatments since the 14th to 28th day after surgery&#58; &#40;1&#41; vehicle &#40;V group&#41;&#59; &#40;2&#41; <span class="elsevierStyleSmallCaps">dl</span>-homocysteine thiolactone &#40;1<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day&#44; oral gavage&#44; H group&#41;&#59; &#40;3&#41; <span class="elsevierStyleSmallCaps">dl</span>-homocysteine thiolactone with folic acid &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day according to a previous study <a class="elsevierStyleCrossRef" href="#bib0330">&#91;29&#93;</a>&#44; oral gavage&#44; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F group&#41;&#59; &#40;4&#41; folic acid &#40;F group&#41;&#46; On the 29th day after CBDL&#44; two series of experiments using four independent treatment groups for each series were performed&#58; first series &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 for each group at the time of CBDL&#41;&#58; measurement of the severity of portosystemic shunting using color microsphere method&#59; second series &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 for each group at the time of CBDL&#41;&#58; &#40;a&#41; BW and hemodynamic measurements including&#58; MAP&#44; HR&#44; PP&#44; CO&#44; CI&#44; SV&#44; SVR&#44; SMA flow&#44; PV flow&#59; &#40;b&#41; measurements of plasma levels of ALT&#44; AST&#44; total bilirubin&#44; BUN&#44; and creatinine&#59; &#40;c&#41; mesenteric protein expressions of VEGF&#44; VEGFR2&#44; p-VEGFR2&#44; PDGF&#44; PDGFR-&#946;&#44; eNOS&#44; p-eNOS&#44; iNOS&#44; COX-1&#44; COX-2 with Western blot analysis&#59; &#40;d&#41; mesenteric vascular density assessment with immunofluorescence&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0095">Hemodynamics</span><p id="par0085" class="elsevierStylePara elsevierViewall">Homocysteine significantly reduced the BW &#40;g&#41; as compared with the vehicle &#40;control&#41; group &#91;vehicle &#40;V&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; vs&#46; homocysteine &#40;H&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; vs&#46; homocysteine plus folic acid &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; vs&#46; folic acid &#40;F&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#93;&#58; 395&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>36&#46;1 vs&#46; 338&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#46;4 vs&#46; 367&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>29&#46;6 vs&#46; 369&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>34&#46;7&#59; V vs&#46; H&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the systemic hemodynamic data of the study groups after the received treatment&#46; Folate significantly elevated MAP and HR&#46; The MAP values &#40;mmHg&#41; after each different treatment were 89&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;4 &#40;V&#41; vs&#46; 83&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;8 &#40;H&#41; vs&#46; 95&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;7 &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; vs&#46; 103&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;2 &#40;F&#41; &#40;V vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; H vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;012&#59; and H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; While HR values &#40;bpm&#41; were 232&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>33&#46;3 &#40;V&#41; vs&#46; 233&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>47&#46;2 &#40;H&#41; vs&#46; 293&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>44&#46;4 &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; vs&#46; 303&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>55&#46;5 &#40;F&#41; &#40;V vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;027&#59; V vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; and H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#46; There were no significant differences in other hemodynamic parameters among the groups&#44; including CO&#44; CI&#44; SV&#44; and SVR &#40;all <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05 among groups&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> shows the splanchnic hemodynamic data of the study groups after the received treatment&#46; There was no significant difference of PP&#44; PV flow and SMA resistance among groups &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; except that homocysteine increased SMA flow &#40;ml&#47;min&#47;100<span class="elsevierStyleHsp" style=""></span>g&#41; as compared with vehicle&#44; which was tended to be reduced by folic acid &#91;6&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;2 &#40;V&#41; vs&#46; 9&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6 &#40;H&#41; vs&#46; 8&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;1 &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; vs&#46; 8&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;6 &#40;F&#41;&#59; V vs&#46; H&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;046&#93;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0100">Liver and renal biochemistry parameters</span><p id="par0100" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> shows the liver and renal biochemistry data &#91;V &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; vs&#46; H &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; vs&#46; F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#93;&#46; Folic acid did not significantly influence ALT&#44; AST or Cr levels but it decreased BUN and total bilirubin levels as compared with the vehicle and homocysteine groups&#58; BUN &#40;mg&#47;dL&#41;&#58; 24&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;8 vs&#46; 23&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;6 vs&#46; 20&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3 vs&#46; 20&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;9&#44; V vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;046&#59; total bilirubin &#40;mg&#47;dL&#41;&#58; 7&#46;31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;00 vs&#46; 8&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;45 vs&#46; 8&#46;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;56 vs&#46; 6&#46;33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;92&#44; H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0105">Shunting and mesenteric window vascular area</span><p id="par0105" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a> depicts the shunting &#91;V &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41; vs&#46; H &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; vs&#46; F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#93; and mesenteric window vascular area ratio &#91;V &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; vs&#46; H &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; vs&#46; F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#93;&#46; Homocysteine significantly increased the shunting ratio &#40;&#37;&#41; &#91;62&#46;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#46;37 &#40;V&#41; vs&#46; 81&#46;49<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;58 &#40;H&#41; vs&#46; 40&#46;51<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;79 &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; vs&#46; 32&#46;80<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;68 &#40;F&#41;&#59; V vs&#46; H&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#59; V vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;029&#59; V vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#59; H vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; and H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93;&#44; which was reduced by folic acid&#46; The mesenteric vascular density &#40;vascular area&#47;mesenteric window area &#40;&#37;&#41;&#58; 7&#46;81<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;09 vs&#46; 11&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;27 vs&#46; 5&#46;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;58 vs&#46; 7&#46;12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;02&#44; H vs&#46; V&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;031&#59; H vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;027&#41; also exhibited the same statistical trend&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0110">Mesenteric proangiogenic factor protein expressions</span><p id="par0110" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a> discloses the protein expressions of mesenteric proangiogenic factors &#91;V &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; vs&#46; H &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; vs&#46; F &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&#93;&#46; There were no significant differences of VEGFR-2&#44; p-VEGFR2 and COX2 expressions&#46; Homocysteine significantly up-regulated VEGF and p-eNOS expressions&#44; which were down-regulated by folic acid &#91;VEGF &#40;&#47;&#946;-actin&#41;&#58; 1&#46;12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;51 &#40;V&#41; vs&#46; 2&#46;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;67 &#40;H&#41; vs&#46; 0&#46;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;40 &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; vs&#46; 0&#46;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;44 &#40;F&#41;&#44; V vs&#46; H&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;026&#59; H vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#59; H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#59; p-eNOS&#58; 1&#46;82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;41 vs&#46; 3&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;83 vs&#46; 1&#46;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;48 vs&#46; 1&#46;49<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;71&#44; V vs&#46; H&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; H vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; H vs&#46; F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93;&#46; Homocysteine up-regulated eNOS expression as compared with vehicle &#91;eNOS&#58; 0&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;16 vs&#46; 0&#46;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;38 vs&#46; 0&#46;79<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;63 vs&#46; 0&#46;68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;28&#44; V vs&#46; H&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030&#93;&#46; There were no significant differences in COX1 expressions among the study groups &#91;COX1&#58; 2&#46;03<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;38 vs&#46; 1&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;71 vs&#46; 0&#46;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;19 vs&#46; 1&#46;09<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;78&#44; V vs&#46; H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#93;&#46; Homocysteine tended to increase the p-VEGFR2&#47;VEGFR2&#44; which was tended to be reduced by folate &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">Hyperdynamic circulatory status is characterized by systemic hypotension and extrahepatic vasodilatation&#46; Compatible with our previous study <a class="elsevierStyleCrossRef" href="#bib0335">&#91;30&#93;</a>&#44; homocysteine did not affect MAP and HR in cirrhotic rats in this study&#46; However&#44; the addition of folic acid to homocysteine and the single administration of folic acid significantly increased MAP and HR in cirrhotic rats&#46; MAP is positively correlated with HR and SV&#46; Since the SV was not influenced by folate&#44; the elevation of MAP might be related to an increase in HR&#46; Although it has been reported that in male smokers&#44; moderate amount of folic acid and vitamins supplement increased the vagal control of HR &#40;&#43;23&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; <a class="elsevierStyleCrossRef" href="#bib0340">&#91;31&#93;</a>&#44; interpolating results from different study designs should be made with caution&#46; Based on the currently available results&#44; we could only note that the hemodynamic influence of folic acid in cirrhotic subjects with portal hypertension has not been reported previously and our finding suggests that folic acid may be able to reverse the profound systemic hypotension in portal hypertension with hyperdynamic circulation&#46; Furthermore&#44; the homocysteine-induced elevation of SMA flow tended to be reduced by folic acid&#46; The reduction of blood flow in splanchnic vascular bed may lessen the drive to develop portosystemic collaterals&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The influences of homocysteine on angiogenesis have been debated&#46; For instance&#44; it has been found that in homocysteine-treated cultured cells&#44; there was a 1&#46;3-fold increased secretion of VEGF <a class="elsevierStyleCrossRef" href="#bib0240">&#91;11&#93;</a>&#46; Another study showed that homocysteine up-regulated VEGF mRNA expression in a dose- and time-dependent manner in macrophages&#44; followed by increased VEGF secretion <a class="elsevierStyleCrossRef" href="#bib0245">&#91;12&#93;</a>&#46; Hyperhomocysteinemia also increased VEGF expression in rat retina <a class="elsevierStyleCrossRef" href="#bib0250">&#91;13&#93;</a>&#46; In contrast&#44; Nagai et al&#46; found that the plasma concentration of homocysteine was inversely correlated with the development of collateral circulation in patients with coronary artery disease <a class="elsevierStyleCrossRef" href="#bib0255">&#91;14&#93;</a>&#46; Moreover&#44; hyperhomocysteinemia impaired ischemia-induced angiogenesis and collateral vascular formation in a rat model with hindlimb ischemia&#44; and that this may have been mediated by reduced NO bioavailability in a hyperhomocysteinemic state <a class="elsevierStyleCrossRef" href="#bib0260">&#91;15&#93;</a>&#46; A recent study also demonstrated that homocysteine induced growth arrest in human endothelial cells <a class="elsevierStyleCrossRef" href="#bib0265">&#91;16&#93;</a>&#46; The differences in these results may be related to the differences in study design with various diseases models and subjects&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Interestingly&#44; the current study found that the shunting degree&#44; which represents the severity of collaterals&#44; was significantly reduced by folic acid in cirrhotic rats&#44; with or without hyperhomocysteinemia&#46; In addition&#44; the mesenteric vascular density and VEGF expression were also down-regulated&#46; Therefore&#44; folic acid reduced shunting in two steps&#58; first&#44; by decreasing splanchnic blood flow and mitigating the stress to form portosystemic collaterals&#59; second&#44; by reducing splanchnic angiogenesis related to VEGF down-regulation&#46; In addition&#44; the mesenteric protein expression of p-eNOS&#44; representing eNOS activation&#44; was also upregulated by homocysteine and reversed by folate&#46; Interestingly&#44; it has been demonstrated in cultured endothelial cells that folic acid activated eNOS via the modulation of eNOS phosphorylation <a class="elsevierStyleCrossRef" href="#bib0345">&#91;32&#93;</a>&#46; Furthermore&#44; eNOS is the downstream effector of VEGF in angiogenesis <a class="elsevierStyleCrossRef" href="#bib0350">&#91;33&#93;</a>&#46; Although previous studies have suggested the anti-angiogenesis effect of homocysteine <a class="elsevierStyleCrossRefs" href="#bib0260">&#91;15&#44;16&#93;</a>&#44; the homocysteine concentrations were 0&#46;2&#8211;5<span class="elsevierStyleHsp" style=""></span>mmol&#47;L&#44; much higher than those in patients with hyperhomocysteinemia&#46; Our previous investigation also revealed that in cirrhotic rats with homocysteinemia&#44; the plasma concentration was 18&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;9<span class="elsevierStyleHsp" style=""></span>&#956;M <a class="elsevierStyleCrossRef" href="#bib0335">&#91;30&#93;</a>&#44; much lower than those of the aforementioned studies <a class="elsevierStyleCrossRefs" href="#bib0260">&#91;15&#44;16&#93;</a>&#46; More portosystemic collaterals were also noted as compared with the vehicle-administered to cirrhotic rats <a class="elsevierStyleCrossRef" href="#bib0335">&#91;30&#93;</a>&#44; supporting the angiogenesis effect of homocysteine in this disease entity&#46; Therefore&#44; folic acid may overcome homocysteine-induced pathological angiogenesis in cirrhosis via down-regulating VEGF-eNOS signaling pathway&#46; Of note&#44; the techniques used to survey the tissue derangements caused by cirrhosis in animal studies are usually invasive and harmful&#44; such as the microsphere method to determine shunting and CD31 immunofluorescent staining for mesenteric angiogenesis&#46; Such methods are not readily applied to patients because of the associated organ damages&#46; Hence&#44; non-invasive modalities have been developed&#44; such as the diffusion-weighted MR imaging&#44; for the prediction of esophageal varices and liver fibrosis <a class="elsevierStyleCrossRefs" href="#bib0355">&#91;34&#8211;37&#93;</a> and they are believed to be promising tools for clinical investigations and applications&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Folic acid also significantly reduced total bilirubin level in cirrhotic rats&#46; Since bilirubin is a surrogate marker of liver function&#44; the finding provides the beneficial evidence of folic acid use in cirrhosis&#46; To sum up&#44; folic acid reversed homocysteine-induced systemic hypotension in cirrhotic rats&#46; The severity of shunting and mesenteric angiogenesis were also mitigated&#44; which may be related to VEGF-eNOS pathway downregulation&#46; Folic acid may be a feasible candidate to alleviate portosystemic collaterals in cirrhosis&#46; Nevertheless&#44; further clinical investigation is required&#46;<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0120">Abbreviations</span><span class="elsevierStyleDefTerm">ALT</span><span class="elsevierStyleDefDescription"><p id="par0135" class="elsevierStylePara elsevierViewall">alanine aminotransferase</p></span><span class="elsevierStyleDefTerm">AST</span><span class="elsevierStyleDefDescription"><p id="par0140" class="elsevierStylePara elsevierViewall">aspartate aminotransferase</p></span><span class="elsevierStyleDefTerm">BUN</span><span class="elsevierStyleDefDescription"><p id="par0145" class="elsevierStylePara elsevierViewall">blood urea nitrogen</p></span><span class="elsevierStyleDefTerm">BW</span><span class="elsevierStyleDefDescription"><p id="par0150" class="elsevierStylePara elsevierViewall">body weight</p></span><span class="elsevierStyleDefTerm">CBDL</span><span class="elsevierStyleDefDescription"><p id="par0155" class="elsevierStylePara elsevierViewall">common bile duct ligation</p></span><span class="elsevierStyleDefTerm">CD31</span><span class="elsevierStyleDefDescription"><p id="par0160" class="elsevierStylePara elsevierViewall">cluster of differentiation 31</p></span><span class="elsevierStyleDefTerm">CI</span><span class="elsevierStyleDefDescription"><p id="par0165" class="elsevierStylePara elsevierViewall">cardiac index</p></span><span class="elsevierStyleDefTerm">CO</span><span class="elsevierStyleDefDescription"><p id="par0170" class="elsevierStylePara elsevierViewall">cardiac output</p></span><span class="elsevierStyleDefTerm">COX</span><span class="elsevierStyleDefDescription"><p id="par0175" class="elsevierStylePara elsevierViewall">cyclooxygenase</p></span><span class="elsevierStyleDefTerm">eNOS</span><span class="elsevierStyleDefDescription"><p id="par0180" class="elsevierStylePara elsevierViewall">endothelial NO synthase</p></span><span class="elsevierStyleDefTerm">F group</span><span class="elsevierStyleDefDescription"><p id="par0185" class="elsevierStylePara elsevierViewall">folic acid-treated group</p></span><span class="elsevierStyleDefTerm">H group</span><span class="elsevierStyleDefDescription"><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSmallCaps">dl</span>-homocysteine thiolactone-treated group</p></span><span class="elsevierStyleDefTerm">H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F group</span><span class="elsevierStyleDefDescription"><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSmallCaps">dl</span>-homocysteine thiolactone with folic acid-treated group</p></span><span class="elsevierStyleDefTerm">HR</span><span class="elsevierStyleDefDescription"><p id="par0200" class="elsevierStylePara elsevierViewall">heart rate</p></span><span class="elsevierStyleDefTerm">MAP</span><span class="elsevierStyleDefDescription"><p id="par0205" class="elsevierStylePara elsevierViewall">mean arterial pressure</p></span><span class="elsevierStyleDefTerm">PDGFR&#946;</span><span class="elsevierStyleDefDescription"><p id="par0210" class="elsevierStylePara elsevierViewall">platelet-derived growth factor receptor &#946;</p></span><span class="elsevierStyleDefTerm">p-eNOS</span><span class="elsevierStyleDefDescription"><p id="par0215" class="elsevierStylePara elsevierViewall">phosphorylated-endothelial nitric oxide synthase</p></span><span class="elsevierStyleDefTerm">PP</span><span class="elsevierStyleDefDescription"><p id="par0220" class="elsevierStylePara elsevierViewall">portal pressure</p></span><span class="elsevierStyleDefTerm">PV</span><span class="elsevierStyleDefDescription"><p id="par0225" class="elsevierStylePara elsevierViewall">portal vein</p></span><span class="elsevierStyleDefTerm">SMA</span><span class="elsevierStyleDefDescription"><p id="par0230" class="elsevierStylePara elsevierViewall">superior mesenteric artery</p></span><span class="elsevierStyleDefTerm">SV</span><span class="elsevierStyleDefDescription"><p id="par0235" class="elsevierStylePara elsevierViewall">stoke volume</p></span><span class="elsevierStyleDefTerm">SVR</span><span class="elsevierStyleDefDescription"><p id="par0240" class="elsevierStylePara elsevierViewall">systemic vascular resistance</p></span><span class="elsevierStyleDefTerm">VEGF</span><span class="elsevierStyleDefDescription"><p id="par0245" class="elsevierStylePara elsevierViewall">vascular endothelial growth factor</p></span><span class="elsevierStyleDefTerm">VEGFR-2</span><span class="elsevierStyleDefDescription"><p id="par0250" class="elsevierStylePara elsevierViewall">VEGF receptor-2</p></span><span class="elsevierStyleDefTerm">V group</span><span class="elsevierStyleDefDescription"><p id="par0255" class="elsevierStylePara elsevierViewall">vehicle-treated group</p></span></span></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0260" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres1233321"
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            1 => array:2 [
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              "titulo" => "Measurement of systemic and portal hemodynamics"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Portosystemic shunting analysis"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Immunofluorescent study for mesenteric vascular density"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Western analysis"
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            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Measurement of biochemical parameters of liver and renal injury"
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              "identificador" => "sec0045"
              "titulo" => "Drugs"
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              "titulo" => "Data analysis"
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              "titulo" => "Hemodynamics"
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            1 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Liver and renal biochemistry parameters"
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            2 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Shunting and mesenteric window vascular area"
            ]
            3 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Mesenteric proangiogenic factor protein expressions"
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          ]
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          "titulo" => "Discussion"
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        6 => array:2 [
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          "titulo" => "Conflict of interest"
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          "titulo" => "Acknowledgements"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-05-17"
    "fechaAceptado" => "2018-11-23"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:5 [
            0 => "Homocysteine"
            1 => "Folic acid"
            2 => "Angiogenesis"
            3 => "Liver cirrhosis"
            4 => "Portosystemic collaterals"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Liver cirrhosis is characterized by increased intrahepatic resistance&#44; splanchnic vasodilation&#47;angiogenesis&#44; and formation of portosystemic collateral vessels&#46; Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage&#46; Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients&#46; It is also known that folic acid supplementation reverses the effects of homocysteine&#46; However&#44; the treatment effect in cirrhosis has yet to be investigated&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation &#40;CBDL&#41;&#46; The CBDL rats randomly received &#40;1&#41; vehicle&#59; &#40;2&#41; <span class="elsevierStyleSmallCaps">dl</span>-homocysteine thiolactone &#40;1<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day&#41;&#59; &#40;3&#41; <span class="elsevierStyleSmallCaps">dl</span>-homocysteine thiolactone plus folic acid &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#59; or &#40;4&#41; folic acid&#46; On the 29th day&#44; hemodynamic parameters&#44; liver and renal biochemistry&#44; protein expressions of proangiogenic factors&#44; mesenteric vascular density and portosystemic shunting were evaluated&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In the cirrhotic rats&#44; homocysteine increased mesenteric vascular density and the severity of shunting&#46; It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor &#40;VEGF&#41; and phosphorylated-endothelial nitric oxide synthase &#40;p-eNOS&#41;&#46; These effects were reversed by folic acid treatment &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Folic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats&#44; which may be related to down-regulation of the VEGF-NO signaling pathway&#46;</p></span>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Shunting ratio and mesenteric vascular density in cirrhotic rats with vehicle &#40;V&#41;&#44; homocysteine &#40;H&#41;&#44; homocysteine plus folic acid &#40;H<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>F&#41; or folic acid &#40;F&#41; administration&#46; The number of each group was 10&#44; 8&#44; 6&#44; 8 for shunting study and 8&#44; 7&#44; 5&#44; 8 for vascular density study&#44; respectively&#46; As compared with vehicle&#44; homocysteine significant increased shunting ratio and vascular area per unit area of mesenteric window &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; which were reversed by folic acid &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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        "texto" => "<p id="par0270" class="elsevierStylePara elsevierViewall">This work was supported by a grant from <span class="elsevierStyleGrantSponsor" id="gs1">Taipei Veterans General Hospital&#44; Taipei&#44; Taiwan</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">VGHUST103-G1-2-3</span>&#41;&#44; which was incorporated in the Veterans General Hospitals University System of Taiwan Joint Research Program&#44; Taiwan&#46; We gratefully acknowledge Chia-chi Lu for her excellent technical assistances&#46; We also thank the Clinical Research Core Laboratory and Animal Center of Department of Medical Research&#44; Taipei Veterans General Hospital for experimental space and facilities&#46;</p>"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2018.12.008

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Year/Month	Html	Pdf	Total

2024 November	7	0	7
2024 October	20	3	23
2024 September	35	2	37
2024 August	23	2	25
2024 July	33	2	35
2024 June	28	1	29
2024 May	25	2	27
2024 April	41	13	54
2024 March	48	4	52
2024 February	39	7	46
2024 January	31	9	40
2023 December	19	6	25
2023 November	38	12	50
2023 October	44	7	51
2023 September	22	4	26
2023 August	33	7	40
2023 July	21	4	25
2023 June	29	3	32
2023 May	47	8	55
2023 April	45	5	50
2023 March	31	2	33
2023 February	23	0	23
2023 January	22	2	24
2022 December	30	10	40
2022 November	75	5	80
2022 October	26	7	33
2022 September	17	17	34
2022 August	11	9	20
2022 July	17	9	26
2022 June	21	8	29
2022 May	10	10	20
2022 April	13	11	24
2022 March	35	10	45
2022 February	25	6	31
2022 January	42	7	49
2021 December	56	8	64
2021 November	25	8	33
2021 October	41	7	48
2021 September	43	12	55
2021 August	33	8	41
2021 July	27	5	32
2021 June	21	5	26
2021 May	18	11	29
2021 April	43	12	55
2021 March	18	9	27
2021 February	14	7	21
2021 January	13	9	22
2020 December	12	11	23
2020 November	13	9	22
2020 October	20	9	29
2020 September	23	13	36
2020 August	17	5	22
2020 July	18	8	26
2020 June	12	6	18
2020 May	18	6	24
2020 April	7	5	12
2020 March	15	6	21
2020 February	35	7	42
2020 January	16	7	23
2019 December	17	11	28
2019 November	12	2	14
2019 October	25	34	59
2019 September	20	51	71
2019 August	43	15	58
2019 July	16	19	35
2019 June	10	16	26
2019 May	5	19	24

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