Published online before print December 29, 2003, doi: 10.1161/01.RES.0000115555.05668.93
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© 2004 American Heart Association, Inc.
Molecular Medicine |
4ß1 Integrin Mediates Selective Endothelial Cell Responses to Thrombospondins 1 and 2 In Vitro and Modulates Angiogenesis In Vivo
From the Laboratory of Pathology (M.J.C., L.Z., J.M.S., J.Z., H.C.K., D.D.R.), National Cancer Institute, National Institutes of Health, Bethesda, Md; Department of Molecular, Cell and Developmental Biology (M.L.I.-A.), UCLA, Los Angeles, Calif; and the Department of Medicine (D.S.A., D.F.M.), University of Wisconsin–Madison, Madison, Wis.
Correspondence to David D. Roberts, PhD, NIH, Building 10 Room 2A33, 10 Center Dr, Bethesda, MD 20892-1500. E-mail droberts{at}helix.nih.gov
We examined the function of 
4ß1 integrin in angiogenesis and in mediating endothelial cell responses to the angiogenesis modulators, thrombospondin-1 and thrombospondin-2. 4ß1 supports adhesion of venous endothelial cells but not of microvascular endothelial cells on immobilized thrombospondin-1, vascular cell adhesion molecule-1, or recombinant N-terminal regions of thrombospondin-1 and thrombospondin-2. Chemotactic activities of this region of thrombospondin-1 and thrombospondin-2 are also mediated by 4ß1, whereas antagonism of fibroblast growth factor-2–stimulated chemotaxis is not mediated by this region. Immobilized N-terminal regions of thrombospondin-1 and thrombospondin-2 promote endothelial cell survival and proliferation in an 4ß1-dependent manner. Soluble 4ß1 antagonists inhibit angiogenesis in the chick chorioallantoic membrane and neovascularization of mouse muscle explants. The latter inhibition is thrombospondin-1–dependent and not observed in explants from thrombospondin-1-/- mice. Antagonizing 4ß1 may in part block proangiogenic activities of thrombospondin-1 and thrombospondin-2, because N-terminal regions of thrombospondin-1 and thrombospondin-2 containing the 4ß1 binding sequence stimulate angiogenesis in vivo. Therefore, 4ß1 is an important endothelial cell receptor for mediating motility and proliferative responses to thrombospondins and for modulation of angiogenesis.
Key Words: adhesion • proliferation • migration • angiogenesis • peptides
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