Abstract
SENP1 (SUMO-specific protease 1) has been shown to be essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) 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-1α 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.
Highlights
SUMOylation has emerged as an important mechanism in the regulation of multiple cellular signaling pathways (1–3)
Hypoxia Induces SENP1 Expression—In a previous study, we found that SENP1 was essential for erythropoietin, a HIF-1␣ target gene, expression under hypoxia conditions (6)
As HIF-1␣ mediates most of the cellular response to hypoxia, we reasoned that the hypoxia-induced SENP1 expression was mediated through the HIF-1␣ signaling
Summary
SUMOylation has emerged as an important mechanism in the regulation of multiple cellular signaling pathways (1–3). We have demonstrated that SENP1 plays an essential role in HIF-1␣-driven VEGF production and angiogenesis in endothelial cells. We determined the expression of SENP1 in HUVEC cells in response to hypoxia by using real-time PCR.
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