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


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 inApoa1bp-/-mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels inApoa1bp-/-mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated inApoa1bp-/-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.
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.).
Renfang
R
Mao
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.).
Shu
S
Meng
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.).
Qilin
Q
Gu
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.).
Raquel
R
Araujo-Gutierrez
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.).
Sandeep
S
Kumar
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.).
Qing
Q
Yan
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.).
Felicidad
F
Almazan
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.).
Keith A
KA
Youker
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.).
Yingbin
Y
Fu
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.).
Henry J
HJ
Pownall
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.).
John P
JP
Cooke
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.).
Yury I
YI
Miller
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.
Longhou
L
Fang
D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis*; D019998:Racemases and Epimerases; D051880:Receptors, Notch / Q000096:biosynthesis*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D015027:Zebrafish
D002352:Carrier Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; C529323:Naxe protein, mouse; D019998:Racemases and Epimerases
AIBP; Notch signaling; angiogenesis; cholesterol; cholesterol efflux; lipid rafts; lipids and lipoprotein metabolism