Renfang Mao1, Shu Meng1, Qilin Gu1, Raquel Araujo-Gutierrez1, Sandeep Kumar1, Qing Yan1, Felicidad Almazan1, Keith A Youker1, Yingbin Fu1, Henry J Pownall1, John P Cooke1, Yury I Miller1, Longhou Fang2. 1. From 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.). 2. From 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.). lhfang@houstonmethodist.org.
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.
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-Itransgenic 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 humanpatients 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.
Authors: M Bodzioch; E Orsó; J Klucken; T Langmann; A Böttcher; W Diederich; W Drobnik; S Barlage; C Büchler; M Porsch-Ozcürümez; W E Kaminski; H W Hahmann; K Oette; G Rothe; C Aslanidis; K J Lackner; G Schmitz Journal: Nat Genet Date: 1999-08 Impact factor: 38.330
Authors: Gina M Peloso; Serkalem Demissie; Dorothea Collins; Daniel B Mirel; Stacey B Gabriel; L Adrienne Cupples; Sander J Robins; Ernst J Schaefer; Margaret E Brousseau Journal: J Lipid Res Date: 2010-09-20 Impact factor: 5.922
Authors: Gen He; Wenjie Luo; Peng Li; Christine Remmers; William J Netzer; Joseph Hendrick; Karima Bettayeb; Marc Flajolet; Fred Gorelick; Lawrence P Wennogle; Paul Greengard Journal: Nature Date: 2010-09-02 Impact factor: 49.962
Authors: Dina A Schneider; Soo-Ho Choi; Colin Agatisa-Boyle; Laurence Zhu; Jungsu Kim; Jennifer Pattison; Dorothy D Sears; Philip L S M Gordts; Longhou Fang; Yury I Miller Journal: J Lipid Res Date: 2018-03-20 Impact factor: 5.922
Authors: Hann Low; Nigora Mukhamedova; Luciano Dos Santos Aggum Capettini; Yining Xia; Irena Carmichael; Stephen H Cody; Kevin Huynh; Michael Ditiatkovski; Ryunosuke Ohkawa; Michael Bukrinsky; Peter J Meikle; Soo-Ho Choi; Seth Field; Yury I Miller; Dmitri Sviridov Journal: Arterioscler Thromb Vasc Biol Date: 2020-08-13 Impact factor: 8.311