Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist

Molecular Pharmacology
Naoyasu UmedaPeter A Campochiaro

Abstract

Integrin alpha(5)beta(1) plays an important role in developmental angiogenesis, but its role in various types of pathologic neovascularization has not been completely defined. In this study, we found strong up-regulation of alpha(5)beta(1) in choroidal neovascularization. Implantation of an osmotic pump delivering 1.5 or 10 microg/h ( approximately 1.8 or 12 mg/kg/day) of 3-(2-{1-alkyl-5-[(pyridin-2-ylamino)-methyl]-pyrrolidin-3-yloxy}-acetylamino)-2-(alkylamino)-propionic acid (JSM6427), a selective alpha(5)beta(1) antagonist, caused significant suppression of choroidal neovascularization; the area of neovascularization was reduced by 33 to 40%. When an osmotic pump delivering 10 microg/h of JSM6427 was implanted 7 days after rupture of Bruch's membrane, there was terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in vascular cells within the neovascularization and significant regression of the neovascularization over the next week. JSM6427 also induced apoptosis of cultured vascular endothelial cells. Fibronectin stimulates phosphorylation of extracellular signal-regulated kinase (ERK) in alpha(5)beta(1)-expressing cells that is blocked by JSM6427. These data suggest that alpha(5)beta(1) plays a rol...Continue Reading

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