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J. Biol. Chem., Vol. 282, Issue 20, 15187-15196, May 18, 2007

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Integrin 91 Directly Binds to Vascular Endothelial Growth Factor (VEGF)-A and Contributes to VEGF-A-induced Angiogenesis^*

Nicholas E. Vlahakis¹, Bradford A. Young, Amha Atakilit, Anne E. Hawkridge, Rachel B. Issaka, Nancy Boudreau, and Dean Sheppard²

From the Lung Biology Center, University of California, San Francisco, California 94143-2922 and Thoracic Disease Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Vascular endothelial growth factor A (VEGF-A) is a potent inducer of angiogenesis. We now show that VEGF-A-induced adhesion and migration of human endothelial cells are dependent on the integrin 91 and that VEGF-A is a direct ligand for this integrin. Adhesion and migration of these cells on the 165 and 121 isoforms of VEGF-A depend on cooperative input from 91 and the cognate receptor for VEGF-A, VEGF receptor 2 (VEGF-R2). Unlike 31or v3 integrins, 91 was also found to bind the 121 isoform of VEGF-A. This interaction appears to be biologically significant, because 91-blocking antibody dramatically and specifically inhibited angiogenesis induced by VEGF-A165 or -121. Together with our previous findings that 91 directly binds to VEGF-C and -D and contributes to lymphangiogenesis, these results identify the integrin 91 as a potential pharmacotherapeutic target for inhibition of pathogenic angiogenesis and lymphangiogenesis.

Received for publication, October 2, 2006 , and in revised form, February 22, 2007.

^* This work was supported by a Mayo Foundation scholarship (to N. E. V.), American Lung Association Research Grant RG-1018-N (to N. E. V.), and by NHLBI Grant R01 HL64353 from National Institutes of Health (to D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Thoracic Disease Research Unit, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-2957; Fax: 507-284-4521; E-mail: vlahakis.nicholas{at}mayo.edu.

² To whom correspondence may be addressed: Lung Biology Center, University of California, P. O. Box 2922, San Francisco, CA 94143-2922. Tel.: 415-514-4269; Fax: 415-514-4278; E-mail: dean.sheppard{at}ucsf.edu.

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