帮忙修改以下英文Background & aims The roles of transforming growth factor β TGFβ in regulating angiogenesis remain controversial Emerging evidence indicates an inhibitory role of TGFβ in angiogenesis contradi

Background and Objectives: The role of transforming growth factor β (TGFβ) in regulating angiogenesis is a matter of debate. Despite the presence of abundant TGFβ and active angiogenesis in the tumor microenvironment, emerging evidence suggests that TGFβ may have an inhibitory effect on angiogenesis. This study aimed to investigate the mechanism by which tumors overcome the anti-angiogenic effect of TGFβ.

Methods: Mouse xenograft models, transgenic zebrafish models, clinical samples, and cell models were utilized to investigate the role of TGFβ in angiogenesis.

Results: Using various in vivo models, we found that TGFβ suppressed physiological angiogenesis in zebrafish but did not affect angiogenesis in mouse hepatoma. Interestingly, the anti-angiogenic effect of TGFβ was abolished in zebrafish treated with HIF1α stabilizer, but was restored in hepatoma xenografts from mice treated with HIF1α inhibitor, indicating that the hypoxic microenvironment may attenuate the anti-angiogenic role of TGFβ. In vitro gain- and loss-of-function analyses demonstrated that TGFβ inhibited the migration and tube formation of endothelial cells (EC) in normoxia but not in hypoxia conditions by upregulating TSP1, a vital anti-angiogenic factor. Moreover, HIF1α induced miR145 expression in response to hypoxia, and miR145 abrogated the role of TGFβ in upregulating TSP1 and repressing angiogenesis by binding to Smad2/3 and inhibiting their expression in EC. Examination of primary EC isolated from human hepatocellular carcinoma (HCC) tissues (TEC) and their adjacent non-tumor liver (NEC) revealed that Smad2, Smad3, and TSP1 were significantly decreased, while miR145 was significantly elevated in TEC. Furthermore, the decreases in Smad3 and TSP1 were negatively correlated with tumor angiogenesis in hepatocellular carcinoma tissues