Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis.
Thrombospondin-1 is a multifunctional protein interacting with several cell surface receptors including integrins. We found that it is a ligand for alpha9beta1 integrin, and has an integrin binding site within its N-terminal domain (NoC1). Interaction of thrombospondin-1 and its recombinant NoC1 domain with alpha9beta1 integrin was confirmed in ELISA and cell adhesion assays. Binding of NoC1 to cells expressing alpha9beta1 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 alpha9beta1 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 alpha9beta1 inhibitors. In summary, our results revealed that alpha9beta1 integrin expressed on microvascular endothelial cells interacts with thrombospondin-1, and this interaction is involved in modulation of angiogenesis.
Staniszewska
Izabela
I
Department of Neuroscience, Center for Neurovirology, Temple University, School of Medicine, Philadelphia, PA 19122, USA.
Zaveri
Shachi
S
Del Valle
Luis
L
Oliva
Isabela
I
Rothman
Vicki L
VL
Croul
Sidney E
SE
Roberts
David D
DD
Mosher
Deane F
DF
Tuszynski
George P
GP
Marcinkiewicz
Cezary
C
D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D020014:K562 Cells; D018919:Neovascularization, Physiologic; D017434:Protein Structure, Tertiary; D019700:Thrombospondin 1 / Q000737:chemistry / Q000502:physiology*
D016023:Integrins; D019700:Thrombospondin 1; C113256:integrin alpha 9 beta 1