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J. Biol. Chem. 279 (3): 2307-2315

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

pH Regulates Vascular Endothelial Growth Factor Binding to Fibronectin

A MECHANISM FOR CONTROL OF EXTRACELLULAR MATRIX STORAGE AND RELEASE*

Adrienne L. Goerges, and Matthew A. Nugent{ddagger}

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Abstract: Hypoxia is one of the major signals that induces angiogenesis. Hypoxic conditions lead to reduced extracellular pH. Vascular endothelial growth factor (VEGF) binding to endothelial cells and the extracellular matrix (ECM) increases at acidic pH (7.0-5.5). These interactions are dependent on heparan sulfate proteoglycans, but do not depend on the presence of VEGF receptors. Here we report that VEGF165 and VEGF121 binding to fibronectin also increased at acidic pH, and that these interactions are further enhanced by the addition of heparin. These results reveal that the accepted non-heparin-binding isoform of VEGF (VEGF121) is converted into a heparin-binding growth factor under acidic conditions. Interestingly, we did not observe increased binding of VEGF to collagen type I at acidic pH in the presence or absence of heparin, indicating that this effect is not a general property of all heparin-binding ECM proteins. The high level of VEGF binding at acidic pH was also rapidly reversed as demonstrated by increased rates of VEGF dissociation from fibronectin and fibronectin-heparin matrices as the pH was raised. The VEGF released from fibronectin retained its ability to stimulate the activation of extracellular-regulated kinase 1/2 in endothelial cells. These results suggest that VEGF may be stored in the extracellular matrix via interactions with fibronectin and heparan sulfate in tissues that are in need of vascularization so that it can aid in directing the dynamic process of growth and migration of new blood vessels.

Received for publication August 1, 2003. Revision received September 22, 2003.

* This work was supported by National Institutes of Health Grant HL56200 and by Training Grant AG00115. 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.

{ddagger} To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, Boston, MA 02118. Tel.: 617-638-4169; Fax: 617-638-5339; E-mail: nugent{at}biochem.bumc.bu.edu.

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