4.7 Article

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

Journal

FASEB JOURNAL
Volume 32, Issue 9, Pages 5051-5062

Publisher

FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201701543RR

Keywords

AT1R; AT2R; p65

Funding

  1. China National Natural Science Foundation [81630002, 91439129, 31430047, 81600263]
  2. Innovative Team Grant from Hubei Province [2017CFA014]
  3. 2016 Top-Notch Innovative Talent Development Project Award from the Bureau of Human Resources and Social Security of Wuhan City
  4. Chinese National Basic Research Program (973 Project) [2013CB531101]
  5. U.S. National Institutes of Health, National Heart, Lung, and Blood Institute [R01 HL121358, R01 HL126729]
  6. Hubei Province Natural Science Programs [2016CFB224, 2014CFA074]
  7. Outstanding Medical Academic Leader Program of Hubei Province

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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 systeminduces the expression of AGGF1 through NF-B, 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 g/ml but not >60 g/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-B 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-B 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-B, 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-B-mediated transcriptional activation of angiogenic factor AGGF1.

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