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

Published

Journal Article

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 beta1 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.

Full Text

Duke Authors

Cited Authors

  • Zhang, X; Kazerounian, S; Duquette, M; Perruzzi, C; Nagy, JA; Dvorak, HF; Parangi, S; Lawler, J

Published Date

  • October 2009

Published In

Volume / Issue

  • 23 / 10

Start / End Page

  • 3368 - 3376

PubMed ID

  • 19528255

Pubmed Central ID

  • 19528255

Electronic International Standard Serial Number (EISSN)

  • 1530-6860

Digital Object Identifier (DOI)

  • 10.1096/fj.09-131649

Language

  • eng

Conference Location

  • United States