Angiotensin II increases angiogenesis by NF‐κB–mediated transcriptional activation of angiogenic factor AGGF1

Abstract

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is involved in vascular development, angiogenesis, specification of hemangioblasts, and differentiation of veins. When mutated, however, it causes Klippel-Trenaunay syndrome, a vascular disorder. In this study, we show that angiotensin II (AngII)-the major effector of the renin-angiotensin system and one of the most important regulators of the cardiovascular system-induces the expression of AGGF1 through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis. AngII significantly up-regulated the levels of AGGF1 mRNA and protein in HUVECs at concentrations of 10-40 μg/ml but not >60 μg/ml. AngII type 1 receptor (AT1R) inhibitor losartan inhibited AngII-induced up-regulation of AGGF1, whereas AT2R inhibitor PD123319 further increased AngII-induced up-regulation of AGGF1. Up-regulation of AGGF1 by AngII was blocked by NF-κB inhibitors, and p65 binds directly to a binding site at the promoter/regulatory region of AGGF1 and transcriptionally activates AGGF1 expression. AngII-induced endothelial tube formation was blocked by small interfering RNAs (siRNAs) for RELA (RELA proto-oncogene, NF-κB subunit)/p65 or AGGF1, and the effect of RELA siRNA was rescued by AGGF1. AngII-induced angiogenesis from aortic rings was severely impaired in Aggf1+/- mice, and the effect was restored by AGGF1. These data suggest that AngII acts as a critical regulator of AGGF1 expression through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis.-Si, W., Xie, W., Deng, W., Xiao, Y., Karnik, S. S., Xu, C., Chen, Q., Wang, Q. K. Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.