| Objective:To investigate the role and molecular mechanism of hypoxia-inducibility factor-1?(HIF-1?)on the differentiation of microvascular pericyte in systemic disorders of systemic sclerosis fibrosis,including pulmonary hypertension(SSc-PAH),skin fibrosis,and pulmonary interstitial fibrosis.Methods:Thirty healthy young rabbits were randomly divided into three groups: group A:normal control group(n=10),group B: SSc model group(n=10),and group C: HIF treated group(n=10).Group A: intraperitoneal injection of mixed solution was given;Group B: intraperitoneal injection of MCT solution and BLM solution;Group C: on the basis of group B modeling method,2-methoxyestradiol(2ME2)solution was intraperitoneally injected.After 21 days,mPAP of pulmonary artery of each rabbit was measured,RVHI of each rabbit was weighed and calculated,skin,pulmonary artery trunk and upper lobe of right lung were stained with HE,and pathological differences of each tissue between the three groups were observed.Microvascular pericytes from skin tissue of 3 groups were extracted and cultured,and the protein contents of-sma and CD31 were determined by Western-blot.Immunohistochemistry was used to detect HIF-1? proteins in lung tissues of each group.Serum levels of HIF-1?,MIF,VEGF and TGF-? were determined by ELISA,and the correlation among the indicators was analyzed.Results:Compared with group B and C,the weight of young rabbits in group A increased significantly,and the difference was statistically significant(P<0.05).There were significant differences in mPAP and RVHI between the three groups,and the differences were statistically significant(P<0.05).mPAP of group B and C were higher than group A,and RVHI of group B was higher than group A.The skin pathology of group B showed the thickening of the dermis and blood vessel wall,andthe thickening degree of group C was less than that of group B.In group B,pulmonary artery stem pathology showed obvious tube wall thickening and lumen stenosis,while in group C,the degree of thickening was less than that in group B.In group B,there was a significant thickening of the pulmonary small blood vessel wall,stenosis in the lumen,vascular remodeling in the pulmonary microvessels,infiltration of inflammatory cells in the alveolar septum,and red blood cells in the alveolar cavity.In group C,there was a limited thickening of the tube wall,and the degree of lumen stenosis was less than that in group B.The histopathological structure of group A showed no obvious abnormality.CD31 was not expressed in the pericytes extracted from the skin tissue of the 3 groups,and the expression of-sma was significantly different,with the highest level in group B,the second highest in group C,and the lowest in group A.HIF-1? protein was strongly positive in the cytoplasm and nucleus of the pulmonary artery endothelial cells in the lung tissues of group B rabbits.The cytoplasm of the pulmonary artery wall endothelial cells in the lung tissue of group C was weakly positive.Lung tissue expression in group A was significantly weaker than that in group B and C.Serum HIF-1?,MIF,VEGF,and TGF-? levels were significantly different among the three groups(P<0.05).HIF-1? level was significantly increased in ssc-pah model,and pericyte differentiation was significantly enhanced.After targeted inhibition of HIF-1?,the expression level of HIF-1?decreased significantly and the function of pericyte differentiation decreased significantly.Correlation analysis showed positive correlation between HIF-1? and MIF,positive correlation between MIF and VEGF,and positive correlation between MIF and TGF-?.Conclusion:1.HIF-1? plays a very important role in the fibrosis of systemic sclerosis.2.HIF-1? may be involved in the pathogenesis of SSc fibrosis by promoting microvascular pericyte differentiation.3.HIF-1? is involved in the pathogenesis of SSc,and its mechanism may be to promote microvascular pericyte differentiation by affecting MIF and then mediating the changes in the levels of VEGF and TGF-?. |
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