HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment

Emerging evidence suggests that TGF beta 1 can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGF beta 1 in the tumor microenvironment. Here, we investigated how tumors overcome the antiangiogenic effect of TGF beta 1. TGF beta 1 treatment suppressed physiologic angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGF beta 1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1 alpha (HIF1 alpha) inhibitor. In contrast, a HIF1 alpha stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the antiangiogenic role of TGF beta 1. Under normoxic conditions, TGF beta 1 inhibited angiogenesis by upregulating antiangiogenic factor thrombospondin 1 (TSP1) in endothelial cells (EC) via TGF beta type I receptor (TGF beta R1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1 alpha induced miR145 expression; miR145 abolished the inhibitory effect of TGF beta 1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma displayed increased miR145 and decreased SMAD3 and TSP1 compared with ECs from adjacent nontumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in hepatocellular carcinoma tissues. Collectively, this study identified that TGF beta 1-TGF beta R1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1 alpha-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.Significance: Suppression of angiogenesis by TGF beta 1 is mediated by TSP1 upregulation in endothelial cells and abrogated by HIF1 alpha-miR145 activity in the hypoxic tumor microenvironment, providing potential targets to remodel the tumor vasculature.