The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online 9 October 2006 doi:10.1084/jem.20060807
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 11, 2495-2507
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ARTICLE

 Integrin signaling is critical for pathological angiogenesis

Ganapati H. Mahabeleshwar1, Weiyi Feng1, David R. Phillips2, and Tatiana V. Byzova1

1 Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, NB50, The Cleveland Clinic Foundation, Cleveland, OH 44195
2 Portola Pharmaceuticals Incorporated, South San Francisco, CA 94080

CORRESPONDENCE Tatiana V. Byzova: byzovat{at}ccf.org

The process of postnatal angiogenesis plays a crucial role in pathogenesis of numerous diseases, including but not limited to tumor growth/metastasis, diabetic retinopathy, and in tissue remodeling upon injury. However, the molecular events underlying this complex process are not well understood and numerous issues remain controversial, including the regulatory function of integrin receptors. To analyze the role of integrin phosphorylation and signaling in angiogenesis, we generated knock-in mice that express a mutant ß3 integrin unable to undergo tyrosine phosphorylation. Two distinct models of pathological angiogenesis revealed that neovascularization is impaired in mutant ß3 knock-in mice. In an ex vivo angiogenesis assay, mutant ß3 knock-in endothelial cells did not form complete capillaries in response to vascular endothelial growth factor (VEGF) stimulation. At the cellular level, defective tyrosine phosphorylation in mutant ß3 knock-in cells resulted in impaired adhesion, spreading, and migration of endothelial cells. At the molecular level, VEGF stimulated complex formation between VEGF receptor-2 and ß3 integrin in wild-type but not in mutant ß3 knock-in endothelial cells. Moreover, phosphorylation of VEGF receptor-2 was significantly reduced in cells expressing mutant ß3 compared to wild type, leading to impaired integrin activation in these cells. These findings provide novel mechanistic insights into the role of integrin–VEGF axis in pathological angiogenesis.

Abbreviations used: EC, endothelial cell; ERK, extracellular signal–regulated kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; von Willebrand factor, vWF.


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