AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling

Abstract

Rationale Angiogenesis improves perfusion to the ischemic tissue following acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that apoA-I binding protein (AIBP)-regulated cholesterol efflux in endothelial cells (ECs) controls zebrafish 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 paper, 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 non-lipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4-stimulated Notch activation in human retinal ECs. Increasing HDL 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.

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

“…For preparation of the tiling arrays, 20 lg RNA, 1.72 lg Random Primers (Invitrogen), and 0.034 lg Oligo (dT) [12][13][14][15][16][17][18] Primers (Invitrogen) were incubated for 10 min at 70°C and 10 min at 25°C to reduce hairpin formation. First-Strand cDNA synthesis was performed in a mixture (60 lL) containing the denatured RNA and the primers, 19 reaction buffer from the SuperScript First-Strand Synthesis System (Invitrogen), 10 mM DTT, 0.5 mM dCTP/ dATP/dGTP, 0.4 mM dTTP, 0.1 mM dUTP, 20 lgÁmL À1 Actinomycin D, and 30 UÁlL À1 SuperScript II Reverse Transcriptase (Invitrogen).…”

AIBP, NAXE, and Angiogenesis

“…1 Deletion of AIBP increased vascular density and improved perfusion in a murine ischemia model. AIBP expression was increased in patients with ischemic cardiomyopathy.…”

“…Using Apoa1bp −/− mice, the present paper has provided evidence that AIBP plays a role in angiogenesis that involves cholesterol metabolism and Notch signaling. 1 These studies suggest AIBP down regulates Notch 1 by a process that depends on γ-secretase activity. γ-Secretase is an intramembrane protease complex composed of four integral membrane proteins: APH1, Nicastrin, PEN2 and presenilin.…”

AIBP, inflammation, and atherosclerosis

“…endothelial cells and macrophages via interaction with apoA-I (6)(7)(8). In zebra fish and mice, AIBP regulated cholesterol levels in endothelial cells that controls angiogenesis via depleting lipid raft content in cell membrane, therefore inhibiting vascular endothelial growth factors receptor 2(VEGFR2) and upregulating the Notch signaling (6,8).…”

“…In zebra fish and mice, AIBP regulated cholesterol levels in endothelial cells that controls angiogenesis via depleting lipid raft content in cell membrane, therefore inhibiting vascular endothelial growth factors receptor 2(VEGFR2) and upregulating the Notch signaling (6,8). Meanwhile, AIBP-mediated cholesterol efflux can also impair the lipid raft-containing toll-like receptor 4 (TLR4), which has been shown to upregulate the MYD88-mediated activation of MAPK and NF-κB signaling as well as downstream inflammatory cytokines (9,10).…”