Mechanisms of Signal Transduction in Vascular Permeability: Potential Targets

La Jolla Institute for Molecular Medicine 4570 Executive Drive, #100, San Diego, CA 92121 (USA) Tel. 1 858 587 8788, Fax 1 831 604 4166 E-Mail beliceiri@ljimm.org Our research has focused on understanding the molecular basis of the requirement for receptors for the extracellular matrix (integrins) during growth factor-induced vascular responses, including angiogenesis and vascular permeability (VP). Significant progress has been made in the understanding of some of the fundamental biological differences between two angiogenic growth factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). For example, we have previously shown that the ligation of specific integrins is required for a sustained intracellular signal (MAP kinase) during bFGF-induced angiogenesis (J Cell Biology 1998;140:1255–1263). As tumors are known to secrete combinations of growth factors such as bFGF and VEGF, it is imperative to understand how each one functions on its own to better understand the effects of combinations of these growth factors on angiogenesis and tumor growth in vivo. This strategy has led to the discovery of differences at the molecular level between these growth factor-induced cascades (Molecular Cell 1999;4:915–924). These results have translated not only into a better understanding of the signaling pathways following integrin ligation and growth factor receptor activation, but it has also uncovered a molecular cue which distinguishes between VEGF-induced blood vessel growth and blood vessel leakage/permeability. This work indicates that the VEGF-induced vascular growth can be distinguished from VEGF-induced VP in mutant mice that are deficient for the Src tyrosine kinase. These results have immediate consequences not only in cancer models in mice but also in mouse models of stroke. In murine stroke models, Src deficiency or blockade of Src activity provided cerebral protection following cerebral ischemia (Nature Med 2001;7: 222–227).