The Expression Of Hypoxia Inducible Factor-1 Alpha And Vascular Endothelial Growth Factor In The Gastric Mucosa Of Portal Hypertensive Rats And The Effection Of Pericardial Devascularization On Them

Background and Objective: Portal hypertension is a common disease. The surgical therapy of portal hypertension stress upper digestive tract bleeding which is a frequent and life-threatening complication of portal hypertension. Portal hypertensive gastropathy(PHG) consists of 10%~70% in all patients with portal hypertension. The bleeding rate caused by portal hypertensive gastropathy is 25%~40%, which is only inferior to oesophageal variceal haemorrhage. It is proved that the primary reason of recurrent hemorrhage after any kinds of devascularization has relation with portal hypertensive gastropathy.The obstacle of the blood circulation in the gastric mucosa is an important pathophysiologic transformation and the pathogenesis of portal hypertensive gastropathy. The hypoxia in the gastric mucosa can induce a series of special genes which are bound up with angiogenesis and hypoxemic metabolism. Hypoxia inducible factor-l(HIF-l) plays an important role in this process. As a exclusive special transcription factor which can work in hypoxia, HIF-1 is involved in regulating the expression of more than sixty genes. HIF-1 is a heterodimeric complex composed of hypoxia inducible factor-1 alpha(HIF-1 α ) and hypoxia inducible factor-1 beta(HIF-1 β ),the formal is the unique oxygen-regulated subunit that determines hypoxia inducible factor-1 activity. Until now vascular endothelial growth factor(VEGF) is the most prominent angiogenic growth factor, whose expression is regulated by some factors, such as hypoxia is the strongest inducer of VEGF expression. CD34 is widely used in marking vascular endothelial cell and detecting the microvessel density(MVD).The specificity of CD34 antigen is higherthan others. In order to evaluate the role of HIF-1 a and VEGF in the occur and development of PHG before and after pericardial devascularization, immunohistochemical technique is applied in examining the expression of HIF-1 a , VEGF and CD34 in the gastric mucosa before and after pericardial devascularization in portal hypertensive rats. It is expected that the study will help us to provide theoretical foundation for the prevention and diagnosis of PHG'Material and Methods: Wistar rats were randomly divided into two groups: 80 rats in prehepatic portal hypertension group(PHPH) and 60 rats in sham-operated group(SO) .The prehepatic portal hypertension models were established by portal vein-ligation, and the sham-operated rats were builts simultaneously. All rats underwent devascularization respectively two weeks later, Gastric was sampled at the time of pre-operation and 7, 14, 30, 60 days after devascularization respectively. Considering death due to operation,8 rats were selected each time. The free portal pressure(FPP) was measured; The expression of HIF-1 a ? VEGF and CD34 were detected by using immunohistology and MVD was counted under CD34 staining. SPSS 10.0 was used to evaluate the statistical significance.Result:l.the result of measuring the FPP: the FPP was significantly higher in the prehepatic portal hypertension group than in the sham-operated group before pericardial devascularization. The FPP in both groups reduced after pericardial devascularization, especially in the prehepatic portal hypertension group(/?<0.01), while the change of the FPP in the sham-operated group was not notable. Then the FPP ascended gradually until it reached the pre-operative level 30 days after pericardial devascularization(/J>0.05).2.the expression of HIF-1 a : The expression level of HIF-1 a before and after pericardial devascularization in the prehepatic portal hypertension group was significantly higher than that in the sham-operated group (/K0.01). The expression level of HIF-1 a before operation was significantly lower than those in 7,14 days after pericardial devascularization respectively in both groups (p<0.01). Though the expression of HIF-1 a in both groups decreased gradually, the level in the prehepatic portal hypertension group was still higher than that in the sham-operated group (p<0.01).3.the expression of VEGF: The expression level of VEGF before operation and 14,,30,60 days after pericardial devascularization in the prehepatic portal hypertension group was significantly higher than that in the sham-operated group (p<0.01). The expression level of VEGF in 14,30 days after pericardial devascularization was significantly higher than the level before operation in both groups(￡<0.01). Though the expression of HIF-1 a in both groups decreased gradually, the level in the prehepatic portal hypertension group was still higher than that in the sham-operated group (p<0.0\). The expression of HIF-1 a. in the sham-operated group reached the pre-operative level 30 and 60 days after pericardial devascularization(/S>0.05).4. the result of measuring the MVD: Compared with the SO rats, the MVD of PHPH rats increased significantly before devascularization(p<0.01). the result of measuring the MVD in 7 days after pericardial devascularization was significantly higher than the level before operation in both groups(p<0.01). It seemed to that the MVD of SO rats decreased, whereas there was a uptrend in the MVD of PHPH rats along with time went by.5.There was close correlation between the expression of HIF-1 a and VEGF in gastric mucosa of rats.Conclusionl.The HIF-1 a and VEGF were ovepressed before operation in the prehepatic portal hypertension group and after pericardial devascularization in both groups, as well as there was a close correlation between the expression of HIF-1 a and VEGF, which indicated that HIF-1 a and VEGF are both involved in the pathogenesis and development ofPHG.2. The MVD of PHPH rats increased significantly pre-operation and enhanced much more after the devascularization. It was suggested that angiogenesis has much to do with the development of hypoxia and the increased bleeding probability in gastric mucosa.3. The FPP was significantly higher in the prehepatic portal hypertension group than in the sham-operated group, which indicated that the portal hypertension may affect the expression of HIF-1 a and VEGF and accordingly involved indirectly in the pathogenesis and development of PHG.4. The expression of HIF-1 a ? VEGF and CD34 were increased significantly after pericardial devascularization in both groups and the histological changes in gastric mucosa aggravated, which suggested pericardial devascularization in itself can have an effect on the expression of HIF-1 a and VEGF through some mechanism, consequently result in the occurrence and development of PHG.