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(Circulation Research. 2007;100:1308.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Interaction of 9ß1 Integrin With Thrombospondin-1 Promotes Angiogenesis

Izabela Staniszewska, Shachi Zaveri, Luis Del Valle, Isabela Oliva, Vicki L. Rothman, Sidney E. Croul, David D. Roberts, Deane F. Mosher, George P. Tuszynski, Cezary Marcinkiewicz

From the From the Department of Neuroscience (I.Z., S.Z., L.D.V., I.O., V.L.R., G.P.T., C.M.), Center for Neurovirology, Temple University, School of Medicine, Philadelphia, Pa; Department of Medicine and Pathobiology (S.E.C.) University of Toronto, Canada; Laboratory of Pathology (D.D.R.), National Cancer Institute, NIH, Bethesda, Md; Department of Medicine (D.F.M.), University of Wisconsin-Madison.

Correspondence to Cezary Marcinkiewicz: Temple University, School of Medicine, Department of Neuroscience, Center for Neurovirology, 1900 N.12th Street, Philadelphia, PA 19122. E-mail cmarcink{at}temple.edu

Thrombospondin-1 is a multifunctional protein interacting with several cell surface receptors including integrins. We found that it is a ligand for 9ß1 integrin, and has an integrin binding site within its N-terminal domain (NoC1). Interaction of thrombospondin-1 and its recombinant NoC1 domain with 9ß1 integrin was confirmed in ELISA and cell adhesion assays. Binding of NoC1 to cells expressing 9ß1 integrin activated signaling proteins such as Erk1/2 and paxillin. Blocking of this integrin by monoclonal antibody and the met-leu-asp-disintegrin inhibited dermal human microvascular endothelial cell proliferation and NoC1-induced migration of these cells. Immunohistochemical studies revealed that 9ß1 is expressed on microvascular endothelium in several organs including skin, lung, heart and brain. NoC1 induced neovascularization in an experimental quail chorioallantoic membrane system and Matrigel plug formation assay in mice. This proangiogenic activity of NoC1 in vivo was inhibited by 9ß1 inhibitors. In summary, our results revealed that 9ß1 integrin expressed on microvascular endothelial cells interacts with thrombospondin-1, and this interaction is involved in modulation of angiogenesis.

Key Words: integrins • thrombospondin • angiogenesis

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