Abstract 501: Angiotensin II Increases Angiogenesis by Nf-κB-mediated Transcriptional Activation of Angiogenic Factor Aggf1

Abstract

Angiogenic factor AGGF1 is involved in the specification of hemangioblasts, vascular development, differentiation of veins, angiogenesis, neointimal formation after vascular injury, and cardiac hypertrophy and heart failure. However, the regulation of the expression of AGGF1 remains incompletely characterized. In this study, we show that vasoconstrictor angiotensin II (AngII), the major effector of the renin-angiotensin system (RAS) and one of the most important regulators of the cardiovascular system, induces the expression of AGGF1 through NF-κB, and up-regulation of AGGF1 plays a key role in AngII-induced angiogenesis. AngII significantly up-regulated the levels of AGGF1 mRNA and protein at low doses (10-40 μM), but not at high doses in HUVECs (>60 μM). AngII receptor AT1R inhibitor losartan inhibited AngII-induced up-regulation of AGGF1, whereas AT2R inhibitor PD123319 further increased AngII-induced up-regulation of AGGF1, suggesting that up-regulation of AGGF1 by AngII was through AT1R. Up-regulation of AGGF1 by AngII was blocked by NF-κB inhibitors PDTC and quinacrine. A binding site for p65 was identified at the 5’-UTR of AGGF1 and shown to bind p65 directly using chromatin immunoprecipitation analysis (CHIP) and electrophoretic mobility shift assays (EMSA). Western blot, real-time RT-PCR and luciferase assays revealed that p65 transcriptionally activated AGGF1 expression. Capillary tube formation assays showed that knockdown of AGGF1 expression inhibited angiogenesis induced by AngII. These data suggest that AngII acts as a critical regulator of AGGF1 expression through NF-κB, and AGGF1 plays a key role in AngII-induced angiogenesis.