Induction of SENP1 in Endothelial Cells Contributes to Hypoxia-driven VEGF Expression and Angiogenesis
Induction of SENP1 in Endothelial Cells Contributes to Hypoxia-driven VEGF Expression and Angiogenesis
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内皮细胞中 SENP1 的诱导有助于缺氧驱动的 VEGF 表达和血管生成
DOI：
10.1074/jbc.m110.164236
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发表时间：
2010-11-19
影响因子：
4.8
通讯作者：
Cheng, Jinke
中科院分区：
文献类型：
--
作者：
Xu, Ying;Zuo, Yong;Cheng, Jinke
SENP1 （sumo特异性蛋白酶1）已被证明在缺氧条件下对缺氧诱导因子1 （HIF-1 α）的稳定性和活性至关重要。然而，在细胞对缺氧的反应中，SENP1激活和缺氧信号是如何协调的尚不清楚。在这里，我们报道了SENP1在内皮细胞中作为缺氧驱动的VEGF生成和血管生成的正调节因子的重要作用。缺氧后内皮细胞中SENP1表达增加。沉默HIF-1 α可阻断SENP1在细胞缺氧反应中的表达。Senp1启动子上缺氧反应元件（HRE）的突变使其在缺氧反应中失活。此外，SENP1表达的沉默减少了VEGF的产生，并取消了内皮细胞的血管生成功能。我们还发现，与野生型相比，Senp1（-/-）小鼠胚胎脑切片中的细长内皮细胞和胚胎肾小球中的血管内皮细胞明显减少。因此，这些结果表明缺氧暗示了一个由SENP1介导的正反馈回路。这种反馈回路在VEGF的产生中是重要的，而VEGF对于内皮细胞的血管生成至关重要。
SENP1 (SUMO-specific protease 1) has been shown to be essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1 alpha) under hypoxia conditions. However, it is unknown how SENP1 activation and hypoxia signaling are coordinated in the cellular response to hypoxia. Here, we report the essential role of SENP1 in endothelial cells as a positive regulator of hypoxia-driven VEGF production and angiogenesis. SENP1 expression is increased in endothelial cells following exposure to hypoxia. Silencing of HIF-1 alpha blocks SENP1 expression in cell response to hypoxia. Mutation of the hypoxia response element (HRE) on the Senp1 promoter abolishes its transactivation in response to hypoxia. Moreover, silencing of SENP1 expression decreases VEGF production and abrogates the angiogenic functions of endothelial cell. We also find that the elongated endothelial cells in embryonic brain section and vascular endothelial cells in embryonic renal glomeruli in Senp1(-/-) mice are markedly reduced than those in wild-type. Thus, these results show that hypoxia implies a positive feedback loop mediated by SENP1. This feedback loop is important in VEGF production, which is essential for angiogenesis in endothelial cells.