TY - JOUR
T1 - An Adam15 amplification loop promotes vascular endothelial growth factor-induced ocular neovascularization
AU - Xie, Bing
AU - Shen, Jikui
AU - Dong, Aling
AU - Swaim, Mara
AU - Hackett, Sean F.
AU - Wyder, Lorenza
AU - Worpenberg, Susanne
AU - Barbieri, Samuel
AU - Campochiaro, Peter A.
PY - 2008/8
Y1 - 2008/8
N2 - Proteins with a disintegrin and a metalloproteinase domain (ADAMs) are a family of membrane-bound proteinases that bind integrins through their disintegrin domain. In this study, we have found modest expression of ADAM15 in pericytes in normal retina and strong up-regulation of ADAM15 in retinal vascular endothelial cells in ischemic retina. Increased expression of vascular endothelial growth factor (VEGF) in the retina in the absence of ischemia also increased ADAM15 levels, and knockdown of Vegf mRNA in ischemic retina reduced Adam15 mRNA. Mice deficient in ADAM15 showed a significant reduction in ischemia-induced retinal neovascularization, choroidal neovascularization at rupture sites in Bruch's membrane, and VEGF-induced subretinal neovascularization. ADAM15-deficient mice also showed reduced levels of VEGF164, VEGF receptor 1, and VEGF receptor 2 in ischemic retina. These data suggest that ADAM15 and VEGF participate in an amplification loop; VEGF increases expression of ADAM15, which in turn increases expression of VEGF and its receptors. Perturbation of the loop by elimination of ADAM15 suppresses ocular neovascularization in 3 different model systems, and thus ADAM15 provides a new therapeutic target for diseases complicated by neovascularization.
AB - Proteins with a disintegrin and a metalloproteinase domain (ADAMs) are a family of membrane-bound proteinases that bind integrins through their disintegrin domain. In this study, we have found modest expression of ADAM15 in pericytes in normal retina and strong up-regulation of ADAM15 in retinal vascular endothelial cells in ischemic retina. Increased expression of vascular endothelial growth factor (VEGF) in the retina in the absence of ischemia also increased ADAM15 levels, and knockdown of Vegf mRNA in ischemic retina reduced Adam15 mRNA. Mice deficient in ADAM15 showed a significant reduction in ischemia-induced retinal neovascularization, choroidal neovascularization at rupture sites in Bruch's membrane, and VEGF-induced subretinal neovascularization. ADAM15-deficient mice also showed reduced levels of VEGF164, VEGF receptor 1, and VEGF receptor 2 in ischemic retina. These data suggest that ADAM15 and VEGF participate in an amplification loop; VEGF increases expression of ADAM15, which in turn increases expression of VEGF and its receptors. Perturbation of the loop by elimination of ADAM15 suppresses ocular neovascularization in 3 different model systems, and thus ADAM15 provides a new therapeutic target for diseases complicated by neovascularization.
KW - Age-related macular degeneration
KW - Angiogenesis
KW - Chemokines
KW - Diabetic retinopathy
KW - Inflammation
KW - Stromal-derived factor-1
KW - Vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=48749110104&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48749110104&partnerID=8YFLogxK
U2 - 10.1096/fj.07-099283
DO - 10.1096/fj.07-099283
M3 - Article
C2 - 18381816
AN - SCOPUS:48749110104
SN - 0892-6638
VL - 22
SP - 2775
EP - 2783
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -