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(Circulation Research. 2006;99:853.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Heparin-II Domain of Fibronectin Is a Vascular Endothelial Growth Factor-Binding Domain

Enhancement of VEGF Biological Activity by a Singular Growth Factor/Matrix Protein Synergism

Errol S. Wijelath, Salman Rahman, Mayumi Namekata, Jacqueline Murray, Tomoaki Nishimura, Zohreh Mostafavi-Pour, Yatin Patel, Yasuo Suda, Martin J. Humphries, Michael Sobel

From the Department of Surgery (E.S.W., M.N., J.M., M.S.), Division of Vascular Surgery, Veterans Affairs Puget Sound Health Care System and the University of Washington School of Medicine, Seattle; The Thrombosis and Vascular Remodeling Laboratory (S.R., Y.P.), Kings College London School of Medicine at St. Thomas Hospital, London, UK; Department of Nanostructure and Advanced Materials (T.N., Y.S.), Graduate School of Science and Engineering and Venture Business Laboratory, Kagoshima University, Japan; and Wellcome Trust Center for Cell-Matrix Research (Z.M.-P., M.J.H.), School of Biological Sciences, University of Manchester, UK.

Correspondence to Errol S. Wijelath, PhD, Research Service-151, 1660 S Columbian Way, Seattle, WA 98108. E-mail errolw{at}u.washington.edu

We describe extracellular interactions between fibronectin (Fn) and vascular endothelial growth factor (VEGF) that influence integrin-growth factor receptor crosstalk and cellular responses. In previous work, we found that VEGF bound specifically to fibronectin (Fn) but not vitronectin or collagens. Herein we report that VEGF binds to the heparin-II domain of Fn and that the cell-binding and VEGF-binding domains of Fn, when physically linked, are necessary and sufficient to promote VEGF-induced endothelial cell proliferation, migration, and Erk activation. Using recombinant Fn domains, the C-terminal heparin-II domain of Fn (type III repeats 13 to 14) was identified as a key VEGF-binding site. Mutation of the heparin-binding residues on FnIII_13–14 abolished VEGF binding, and peptides corresponding to the heparin-binding sequences in FnIII_13–14 inhibited VEGF binding to Fn. Fn fragments containing both the ₅ß₁ integrin-binding domain (III 9 to 10) and the VEGF-binding domain (III 13 to 14) significantly enhanced VEGF-induced EC migration and proliferation and induced strong phosphorylation of the VEGF receptor and Erk. Neither the cell-binding or VEGF-binding fragment of Fn alone had comparable VEGF-promoting effects. These results suggest that the mechanism of VEGF/Fn synergism is mediated extracellularly by the formation of a novel VEGF/Fn complex requiring both the cell-binding and VEGF-binding domains linked in a single molecular unit. These data also highlight a new function for the Fn C-terminal heparin-binding domain that may have important implications for angiogenesis and tumor growth.

Key Words: endothelial cell differentiation • endothelial cell growth • endothelial cells • fibronectin • integrins • signal transduction • vascular endothelial growth factor • vascular endothelial growth factor receptors

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