ADAM9 is involved in pathological retinal neovascularization.
Pathological ocular neovascularization, caused by diabetic retinopathy, age-related macular degeneration, or retinopathy of prematurity, is a leading cause of blindness, yet much remains to be learned about its underlying causes. Here we used oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) to assess the contribution of the metalloprotease-disintegrin ADAM9 to ocular neovascularization in mice. Pathological neovascularization in both the OIR and CNV models was significantly reduced in Adam9(-/-) mice compared to wild-type controls. In addition, the level of ADAM9 expression was strongly increased in endothelial cells in pathological vascular tufts in the OIR model. Moreover, tumor growth from heterotopically injected B16F0 melanoma cells was reduced in Adam9(-/-) mice compared to controls. In cell-based assays, the overexpression of ADAM9 enhanced the ectodomain shedding of EphB4, Tie-2, Flk-1, CD40, VCAM, and VE-cadherin, so the enhanced expression of ADAM9 could potentially affect pathological neovascularization by increasing the shedding of these and other membrane proteins from endothelial cells. Finally, we provide the first evidence for the upregulation of ADAM9-dependent shedding by reactive oxygen species, which in turn are known to play a critical role in OIR. Collectively, these results suggest that ADAM9 could be an attractive target for the prevention of proliferative retinopathies, CNV, and cancer.
Guaiquil
Victor
V
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA.
Swendeman
Steven
S
Yoshida
Tsunehiko
T
Chavala
Sai
S
Campochiaro
Peter A
PA
Blobel
Carl P
CP
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000009:adverse effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015861:Retinal Neovascularization / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D051722:ADAM Proteins; C498316:Adam9 protein, mouse; D010100:Oxygen