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Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level

Xuefeng Zhang^*,1, Shideh Kazerounian^*, Mark Duquette^*, Carole Perruzzi^*, Janice A. Nagy^*, Harold F. Dvorak^*, Sareh Parangi and Jack Lawler^*,2

^* Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA; and

Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

² Correspondence: Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., EC/CLS-503, Boston, MA 02215, USA. E-mail: jlawler{at}bidmc.harvard.edu

Vascular endothelial growth factor (VEGF) is a well-established stimulator of vascular permeability and angiogenesis, whereas thrombospondin-1 (TSP-1) is a potent angiogenic inhibitor. In this study, we have found that the TSP-1 receptors CD36 and β1 integrin associate with the VEGF receptor 2 (VEGFR2). The coclustering of receptors that regulate angiogenesis may provide the endothelial cell with a platform for integration of positive and negative signals in the plane of the membrane. Thus, this complex may represent a molecular switch that regulates angiogenesis and determines endothelial cell behavior. In this context, physiological levels of TSP-1 appear to support VEGFR2 function on both the cellular and tissue level, because phosphorylation of VEGFR2 and vascular permeability in response to VEGF are decreased in TSP-1-null mice and isolated endothelial cells. A therapeutic agent based on the antiangiogenic domain of TSP-1, designated 3TSR (for three TSP-1 type 1 repeats), has significant antiangiogenic and antitumor efficacy. Systemic treatment of wild-type mice with 3TSR significantly decreased VEGF-induced permeability. Consistent with this result, VEGF-stimulated phosphorylation of VEGFR2 was also significantly decreased in lung extracts from 3TSR-treated mice. Moreover, 3TSR significantly decreased VEGF-stimulated VEGFR2 phosphorylation in human dermal microvascular endothelial cells in culture. Taken together, the results indicate that TSP-1 and 3TSR modulate the function of VEGFR2.—Zhang, X., Kazerounian, S., Duquette, M., Perruzzi, C., Nagy, J. A., Dvorak, H. J., Parangi, S., and Lawler, J. Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level.

Key Words: KDR • angiogenesis • integrin • CD36 • VEGFR2

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