Emerging evidence suggests that transforming growth factor β1 (TGFβ1) can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the anti-angiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiological angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the anti-angiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating anti-angiogenic factor thrombospondin 1 (TSP1) in endothelial cells (ECs) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced microRNA-145 (miR145) expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma (HCC) displayed increased miR145 and decreased SMAD3 and TSP1 compared to ECs from adjacent non-tumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in HCC tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.

中文翻译：

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HIF1α 抵消内皮细胞中 TGFβ1 驱动的 TSP1 表达，刺激缺氧肿瘤微环境中的血管生成


新的证据表明，转化生长因子 β1 (TGFβ1) 可以抑制血管生成，这与肿瘤微环境中活跃的血管生成和高丰度 TGFβ1 的共存相矛盾。在这里，我们研究了肿瘤如何克服 TGFβ1 的抗血管生成作用。 TGFβ1 治疗抑制鸡绒毛尿囊膜和斑马鱼模型中的生理性血管生成，但不影响小鼠肝癌异种移植物中的血管生成。缺氧诱导因子 1α (HIF1α) 抑制剂在小鼠异种移植物中恢复了 TGFβ1 对血管生成的抑制作用。相比之下，HIF1α 稳定剂消除了斑马鱼的血管生成，表明缺氧可能减弱 TGFβ1 的抗血管生成作用。在常氧条件下，TGFβ1 通过 TGFβ I 型受体 (TGFβR1)-SMAD2/3 信号传导上调内皮细胞 (EC) 中的抗血管生成因子血小板反应蛋白 1 (TSP1)，从而抑制血管生成。在缺氧微环境中，HIF1α 诱导 microRNA-145 (miR145) 表达； miR145 通过结合并抑制 SMAD2/3 表达并随后降低 EC 中的 TSP1 水平，消除了 TGFβ1 对血管生成的抑制作用。与来自邻近非肿瘤肝脏的 EC 相比，从人肝细胞癌 (HCC) 中分离的原代 EC 表现出 miR145 增加和 SMAD3 和 TSP1 减少。 EC 中 SMAD3 或 TSP1 的减少与 HCC 组织中血管生成的增加有关。总的来说，这项研究发现 EC 中的 TGFβ1-TGFβR1-SMAD2/3-TSP1 信号传导抑制血管生成。这种抑制可以通过缺氧-HIF1α-miR145轴来规避，从而阐明了缺氧促进血管生成的机制。