Src kinase activity was found to protect endothelial cells from apoptosis during vascular endothelial growth factor (VEGF)-, but not basic fibroblast growth factor (bFGF)-, mediated angiogenesis in chick embryos and mice. In fact, retroviral targeting of kinase-deleted Src to tumor-associated blood vessels suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice deficient in pp60c-src or pp62c-yes showed no VEGF-induced vascular permeability (VP), yet fyn-/- mice displayed normal VP. In contrast, inflammation-mediated VP appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated angiogenesis requires SFK activity in general, whereas the VP activity of VEGF specifically depends on the SFKs, Src, or Yes.

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Abstract-Crosstalk between integrins and growth factor receptors are an important signaling mechanism to provide specificity during normal development and pathological processes in vascular biology. Evidence from several model systems demonstrates the physiological importance of the coordination of signals from growth factors and the extracellular matrix to support cell proliferation, migration, and invasion in vivo. Several examples of crosstalk between these two important classes of receptors indicate that integrin ligation is required for growth factor-induced biological processes. Furthermore, integrins can directly associate with growth factor receptors, thereby regulating the capacity of integrin/growth factor receptor complexes to propagate downstream signaling. Recent data suggest that antagonists of ␣ v integrins can provide a therapeutic benefit in human cancer patients, whereas knockout mice lacking specific integrins can provide an interesting insight into the role of integrins during development. This review will focus on the biological importance of integrin and growth factor receptor crosstalk that occurs during cell growth, migration, and invasion as well as in endothelial cells during angiogenesis. Key Words: integrins Ⅲ growth factor receptors Ⅲ cell migration/invasion Ⅲ angiogenesis R ecent work from a number of laboratories has demonstrated that cell adhesion receptors and growth factor receptors are important molecular determinants in providing specificity for signaling during development and/or during pathological processes. Although integrins and growth factor receptors can independently propagate intracellular signals, the synergy of signals provided by the extracellular matrix (ECM) and growth factors appears to regulate complex processes, including blood vessel development during embryogenesis as well as tumor growth/metastasis and angiogenesis in the adult. Analysis of the crosstalk between the biochemical pathways mediated by integrins and growth factor receptors may ultimately lead to a better understanding of the cell biological processes underlying normal development and the progression of pathological conditions. Several excellent reviews on integrin-mediated 1-4 and growth factor receptormediated signal transduction 5,6 have been recently published; therefore, this review will focus on the evidence for crosstalk between integrins and growth factor receptors in cell biology. These in vitro studies help provide an important insight into the role of integrins in more complex biological questions in vascular biology. This will be followed by an analysis of the recent progress on growth factor-induced angiogenesis as a paradigm for the study of the crosstalk between growth factor receptors and integrins in intact tissues. Recent work provides clinical data on the therapeutic benefit of ␣ v integrin antagonists, whereas studies of knockout mice, lacking various integrins, provide insight into the role of integrins during the embryonic development of the mouse vasculature. Model systems...

Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.

Vascular endothelial growth factor (VEGF) promotes vascular permeability (VP) and neovascularization, and is required for development. We find that VEGF-stimulated Src activity in chick embryo blood vessels induces the coupling of focal adhesion kinase (FAK) to integrin αvβ5, a critical event in VEGF-mediated signaling and biological responsiveness. In contrast, FAK is constitutively associated with β1 and β3 integrins in the presence or absence of growth factors. In cultured endothelial cells, VEGF, but not basic fibroblast growth factor, promotes the Src-mediated phosphorylation of FAK on tyrosine 861, which contributes to the formation of a FAK/αvβ5 signaling complex. Moreover, formation of this FAK/αvβ5 complex is significantly reduced in pp60c-src-deficient mice. Supporting these results, mice deficient in either pp60c-src or integrin β5, but not integrin β3, have a reduced VP response to VEGF. This FAK/αvβ5 complex was also detected in epidermal growth factor-stimulated epithelial cells, suggesting a function for this complex outside the endothelium. Our findings indicate that Src can coordinate specific growth factor and extracellular matrix inputs by recruiting integrin αvβ5 into a FAK-containing signaling complex during growth factor–mediated biological responses.