Angiopoietin-1 guides directional angiogenesis through integrin αvβ5 signaling for recovery of ischemic retinopathy.
Retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) are ischemic retinal diseases caused by insufficient vascular network formation and vascular regression in addition to aberrant angiogenesis. We examined the role of angiopoietin-1 (Ang1) in retinal vascular network formation during postnatal development using Ang1 gain- and loss-of-function mouse models, and tested the effects of intraocular administration of Ang1 in an oxygen-induced retinopathy (OIR) mouse model that mimics cardinal features of ROP and PDR. We observed that Ang1 plays a substantial role in the formation of the retinal vascular network during postnatal development and that Ang1 supplementation can rescue vascular retinopathies by simultaneously promoting healthy vascular network formation and inhibiting subsequent abnormal angiogenesis, vascular leakage, and neuronal dysfunction in the retinas of the OIR model. We attribute these Ang1-induced effects to a dual signaling pathway-Tie2 signaling in the vascular region and integrin αvβ5 signaling in the astrocytes. The activation of integrin αvβ5 signaling promoted fibronectin accumulation and radial distribution along the sprouting endothelial cells, which consequently stimulated guided angiogenesis in the retina. These findings shed light on the role of Ang1 in the recovery of ischemic retinopathies such as ROP, PDR, and retinal vascular occlusive disease.
National Research Laboratory of Vascular Biology and Stem Cells, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Junyeop
J
Lee
Kyung Eun
KE
Kim
Dong-Kyu
DK
Choi
Jeon Yeob
JY
Jang
Ji-Jung
JJ
Jung
Hiroshi
H
Kiyonari
Go
G
Shioi
Woohyok
W
Chang
Toshio
T
Suda
Naoki
N
Mochizuki
Yoshikazu
Y
Nakaoka
Issei
I
Komuro
Ook-Joon
OJ
Yoo
Gou Young
GY
Koh
D042683:Angiopoietin-1 / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D042683:Angiopoietin-1; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5