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First published on March 9, 2006; DOI: 10.1124/mol.105.020941

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Received for publication November 22, 2005.
Revised March 8, 2006.
Accepted for publication March 9, 2006.

Suppression and Regression of Choroidal Neovascularization by Systemic Administration of an {alpha}5{beta}1 Integrin Antagonist

Naoyasu Umeda 1, Shu Kachi 1, Hideo Akiyama 1, Grit Zahn 2, Doerte Vossmeyer 2, Roland Stragies 2, Peter Campochiaro 3*

1 Johns Hopkins 2 Jerini 3 Johns Hopkins University School of Medicine

* Address correspondence to: E-mail: pcampo{at}jhmi.edu

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 upregulation of {alpha}5{beta}1 in choroidal neovascularization. Implantation of an osmotic pump delivering 1.5 or 10 µg/hour (~1.8 or 12 mg/kg/day) of 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 µg/hour of JSM6427 was implanted 7 days after rupture of Bruch's membrane, there was 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 and this is blocked by JSM6427.These data suggest that {alpha}5{beta}1 plays a role in the development and maintenance of choroidal neovascularization and provides a target for therapeutic intervention.


Key words: Mechanisms of cell killing/apoptosis, Angiogenesis


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