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(Circulation Research. 2007;101:570.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Mechanisms of Integrin–Vascular Endothelial Growth Factor Receptor Cross-Activation in Angiogenesis

Ganapati H. Mahabeleshwar, Weiyi Feng, Kumar Reddy, Edward F. Plow, Tatiana V. Byzova

From the Department of Molecular Cardiology, The Cleveland Clinic, Ohio.

Correspondence to Tatiana V. Byzova, Department of Molecular Cardiology, The Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail byzovat{at}ccf.org

The functional responses of endothelial cells are dependent on signaling from peptide growth factors and the cellular adhesion receptors, integrins. These include cell adhesion, migration, and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. This study identifies the molecular requirements for the cross-activation between ß₃ integrin and tyrosine kinase receptor 2 for vascular endothelial growth factor (VEGF) receptor (VEGFR-2) on endothelium. The relationship between VEGFR-2 and ß₃ integrin appears to be synergistic, because VEGFR-2 activation induces ß₃ integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF-induced tyrosine phosphorylation of VEGFR-2. We demonstrate here that adhesion- and growth factor–induced ß₃ integrin tyrosine phosphorylation are directly mediated by c-Src. VEGF-stimulated recruitment and activation of c-Src and subsequent ß₃ integrin tyrosine phosphorylation are critical for interaction between VEGFR-2 and ß₃ integrin. Moreover, c-Src mediates growth factor–induced ß₃ integrin activation, ligand binding, ß₃ integrin-dependent cell adhesion, directional migration of endothelial cells, and initiation of angiogenic programming in endothelial cells. Thus, the present study determines the molecular mechanisms and consequences of the synergism between 2 cell surface receptor systems, growth factor receptor and integrins, and opens new avenues for the development of pro- and antiangiogenic strategies.

Key Words: angiogenesis • endothelial cell • ß₃ integrin signaling • vascular endothelial growth factor receptor • extracellular matrix proteins

Related Article:

Substrate Matters: Reciprocally Stimulatory Integrin and VEGF Signaling in Endothelial Cells

Ebba Brakenhielm
Circ. Res. 2007 101: 536-538. [Full Text] [PDF]

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