PUBLICATION
AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling
- Authors
- Meng, S., Mao, R., Gu, Q., Araujo-Gutierrez, R., Kumar, S., Yan, Q., Almazan, F., Youker, K.A., Fu, Y., Pownall, H.J., Cooke, J.P., Miller, Y.I., Fang, L.
- ID
- ZDB-PUB-170323-14
- Date
- 2017
- Source
- Circulation research 120(11): 1727-1739 (Journal)
- Registered Authors
- Fang, Longhou, Gu, Qilin, Miller, Yury
- Keywords
- AIBP, Notch signaling, angiogenesis, cholesterol, cholesterol efflux, lipid rafts, lipids and lipoprotein metabolism
- MeSH Terms
-
- Amyloid Precursor Protein Secretases/physiology*
- Animals
- Carrier Proteins/biosynthesis*
- Hindlimb/blood supply
- Hindlimb/metabolism
- Hindlimb/pathology
- Humans
- Ischemia/metabolism
- Ischemia/pathology
- Mice
- Mice, Knockout
- Neovascularization, Physiologic/physiology*
- Phosphoproteins/biosynthesis*
- Receptors, Notch/biosynthesis*
- Retina/metabolism
- Retina/pathology
- Signal Transduction/physiology*
- Up-Regulation/physiology*
- Zebrafish
- PubMed
- 28325782 Full text @ Circ. Res.
Citation
Meng, S., Mao, R., Gu, Q., Araujo-Gutierrez, R., Kumar, S., Yan, Q., Almazan, F., Youker, K.A., Fu, Y., Pownall, H.J., Cooke, J.P., Miller, Y.I., Fang, L. (2017) AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling. Circulation research. 120(11):1727-1739.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping