Inhibition of retinal neovascularization by soluble EphA2 receptor.
Eph receptor tyrosine kinases (RTKs) and their ligands, known as ephrins, play an important role in vascular remodeling during embryogenesis, but their functions in adult angiogenesis are just beginning to be investigated. In this report, we investigated the effect of blocking EphA receptor activation on VEGF-induced angiogenic responses of cultured retinal endothelial cells and on retinal neovascularization in a rodent model of retinopathy of prematurity (ROP). Soluble EphA2-Fc receptors inhibited ephrin-A1 ligand or VEGF-induced BRMEC migration and tube formation without affecting proliferation in vitro. Since EphA2-Fc receptors can inhibit activation of multiple EphA receptors, the specific role of EphA2 receptor in angiogenesis was further investigated in EphA2-deficient endothelial cells. Loss of EphA2 in endothelial cells leads to defective cell migration and assembly in response to either ephrin-A1 or VEGF. Finally, a significant reduction in the severity of abnormal retinal neovascularization was observed in the eyes treated with soluble EphA2-Fc receptors, yet the normal total retinal vascular area was not significantly changed. Because soluble Eph receptor significantly inhibited pathologic retinal angiogenesis without affecting normal intraretinal vessels, it may be a promising agent for treatment of retinal angiogenesis in a number of human ocular diseases.
Chen
Jin
J
Department of Medicine, Division of Rheumatology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. jin.chen@vanderbilt.edu
Hicks
Donna
D
Brantley-Sieders
Dana
D
Cheng
Nikki
N
McCollum
Gary W
GW
Qi-Werdich
Xiang
X
Penn
John
J
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D036382:Ephrin-A1 / Q000037:antagonists & inhibitors; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007231:Infant, Newborn; D007267:Injections; D051381:Rats; D017207:Rats, Sprague-Dawley; D036104:Receptor, EphA2 / Q000008:administration & dosage* / Q000032:analysis; D012160:Retina / Q000187:drug effects*; D015861:Retinal Neovascularization / Q000517:prevention & control*; D012171:Retinal Vessels / Q000201:enzymology; D012178:Retinopathy of Prematurity / Q000150:complications*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D036382:Ephrin-A1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D036104:Receptor, EphA2