Control of angiogenesis by AIBP-mediated cholesterol efflux

Abstract

Cholesterol is a structural component of the cell, indispensable for normal cellular function, but its excess often leads to abnormal proliferation, migration, inflammatory responses and/or cell death. To prevent cholesterol overload, ATP-binding cassette (ABC) transporters mediate cholesterol efflux from the cells to apolipoprotein A-I (ApoA-I) and to the ApoA-I-containing high-density lipoprotein (HDL)1-3. Maintaining efficient cholesterol efflux is essential for normal cellular function4-6. However, the role of cholesterol efflux in angiogenesis and the identity of its local regulators are poorly understood. Here we show that ApoA-I binding protein (AIBP) accelerates cholesterol efflux from endothelial cells (EC) to HDL and thereby regulates angiogenesis. AIBP/HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 dimerization and signaling, and inhibits VEGF-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Remarkably, Aibp regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell autonomous regulator of zebrafish angiogenesis. Aibp knockdown results in dysregulated sprouting/branching angiogenesis, while forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1/Abcg1-deficient embryos, and cholesterol levels are increased in Aibp-deficient and Abca1/Abcg1-deficient embryos. Our findings demonstrate that secreted AIBP positively regulates cholesterol efflux from EC and that effective cholesterol efflux is critical for proper angiogenesis.

AIBP: A Novel Molecule at the Interface of Cholesterol Transport, Angiogenesis, and Atherosclerosis

“…We showed that this change of cholesterol efflux is a spatiotemporal-dependent event that occurs in development during zebrafish angiogenesis. 2 Most studies on cholesterol efflux associated with atherosclerosis were done in macrophages, so whether AIBP accelerates cholesterol efflux from these particular cells merits further investigation. Additionally, maintenance of cholesterol homeostasis in ECs appears critical for proper vascular function.…”

“…2 This inhibitory effect of AIBP depends on cholesterol transporter ABCG1, which is responsible for cholesterol removal in ECs. 66 Accordingly, loss of ABCG1 abolishes the enhanced effect of AIBP on cholesterol efflux in ECs.…”

“…Increased cholesterol levels in ECs can result in elevated levels of lipid rafts and their associated membrane receptor activation, leading to inflammation and/or hyperproliferation and angiogenesis. 2,64 This should be avoided in the plaque microenvironment, where intraplaque angiogenesis may incur vulnerability and culminate in its rupture. 65 It will be important to investigate if the enhancement effect of AIBP on cholesterol removal may improve the functionality of HDL in vivo and mitigate the development of atherosclerosis and CVD in at-risk patients.…”

“…[57][58][59] We have recently reported that AIBP demonstrates a capability to enhance cholesterol efflux of HDL and therefore may fulfill the role of boosting HDL functionality ( Figure 1). 2 AIBP is a secreted protein discovered in a screen of proteins that interact with apoA-I. 60 Human AIBP is abundantly expressed in a majority of tissues that govern secretions.…”

“…Furthermore, AIBP inhibits vascular endothelial growth factor receptor 2 activation in endothelial cells and limits angiogenesis. 2 The following discusses the prospect of using AIBP as a novel therapeutic approach for the treatment of CAD.L. Zhu, B.S.…”