AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling. Issue 11 (26th May 2017)

• Record Type: Journal Article
• Authors: Mao, Renfang; Meng, Shu; Gu, Qilin; Araujo-Gutierrez, Raquel; Kumar, Sandeep; Yan, Qing; Almazan, Felicidad; Youker, Keith A.; Fu, Yingbin; Pownall, Henry J.; Cooke, John P.; Miller, Yury I.; Fang, Longhou
• Is Part Of: Circulation research. Volume 120:Issue 11(2017)
• Publication Date: 2017-05-26
• Subjects: AIBP -- angiogenesis -- cholesterol -- cholesterol efflux -- lipid rafts -- Notch signaling -- lipids and lipoprotein metabolism; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.309754
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: : Angiogenesis improves perfusion to the ischemic tissue after acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that AIBP (apolipoprotein A-I [apoA-I]–binding protein)–regulated cholesterol efflux in endothelial cells controls zebra fish embryonic angiogenesis. Objective: : This study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions and to explore the underlying molecular mechanism. Methods and Results: : In this article, we report the generation of AIBP knockout ( Apoa1bp −/− ) mice, which are characterized of accelerated postnatal retinal angiogenesis. Mechanistically, AIBP triggered relocalization of γ-secretase from lipid rafts to nonlipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4 (delta-like ligand 4)-stimulated Notch activation in human retinal endothelial cells. Increasing high-density lipoprotein levels in Apoa1bp −/− mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels in Apoa1bp −/− mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated in Apoa1bp −/− mice and associated with a profound inhibition of Notch activation and reduced expression of downstream targets. Furthermore, loss of AIBP increased vascular density and facilitated the recovery of blood vessel perfusion function in a murine hindlimb ischemia model. In addition, AIBP expression was significantly increased in human patients with ischemic cardiomyopathy. Conclusions: : Our data reveal a novel mechanistic connection between AIBP-mediated cholesterol metabolism and Notch signaling, implicating AIBP as a possible druggable target to modulate angiogenesis under pathological conditions. Abstract : Supplemental Digital Content is available in the text.