Published online before print June 20, 2002, doi: 10.1161/01.RES.0000026420.22406.79
© 2002 American Heart Association, Inc.
Molecular Medicine |
Novel Vascular Endothelial Growth Factor Binding Domains of Fibronectin Enhance Vascular Endothelial Growth Factor Biological Activity
From the Department of Molecular Biology (E.S.W., J.M., A.I., K.S., C.C., W.P.H.), The Hope Heart Institute, Seattle, Wash; the Department of Surgery (E.S.W., J.M., K.S., M.S.), Division of Vascular Surgery, University of Washington School of Medicine and VA Puget Sound Health Care System, Seattle, Wash; Coagulation Research Laboratory (S. Rahman, Y.P., G.F.S.), GKT Medical School, St Thomas Hospital, London, UK; Division of Cardiothoracic Surgery (S.A.), University of Colorado, Denver, Colo; and the Division of Hematology-Oncology (S. Rafii), Cornell Medical College, New York, NY.
Correspondence to E.S. Wijelath, PhD, Research Service-151, VA Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108. E-mail wijelath{at}u.washington.edu
Interactions between integrins and growth factor receptors play a critical role in the development and healing of the vasculature. This study mapped two binding domains on fibronectin (FN) that modulate the activity of the angiogenic factor, vascular endothelial growth factor (VEGF). Using solid-phase assays and surface plasmon resonance analysis, we identified two novel VEGF binding domains within the N- and C-terminus of the FN molecule. Native FN bound to VEGF enhanced endothelial cell migration and mitogen-activated protein (MAP) kinase activity, but FN that is devoid of the VEGF binding domains failed to do so. Coprecipitation studies confirmed a direct physical association between VEGF receptor-2 (Flk-1) and the FN integrin, 
5ß1, which required intact FN because FN fragments lacking the VEGF binding domains failed to support receptor association. Thrombin-activated platelets released intact VEGF/FN complexes, which stimulated endothelial cell migration and could be inhibited by soluble high affinity VEGF receptor 1 and antibodies to 5ß1 integrin. This study demonstrates that FN is potentially a physiological cofactor for VEGF and provides insights into mechanisms by which growth factor receptors and integrins cooperate to influence cellular behavior.
Key Words: vascular endothelial growth factor • fibronectin • binding domains • integrins • endothelial cells
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