AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling
Renfang Mao1, Shu Meng1, Qilin Gu1
1From the Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences (R.M., S.M., Q.G., R.A.-G., Q.Y., J.P.C., L.F.), Houston Methodist DeBakey Heart and Vascular Center, Department of Cardiology (R.A.-G., K.A.Y.), Department of Bioenergetics (H.J.P.), Houston Methodist Research Institute, TX; Department of Ophthalmology, Baylor College of Medicine, Houston, TX (S.K., Y.F.); and Department of Medicine, University of California, San Diego, La Jolla (F.A., Y.I.M.).
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.
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:10Mechanism of Angiogenesis
01:16TGF - β Signaling Pathway
01:20The JAK-STAT Signaling Pathway