VEGF actions are mediated through binding to two receptor tyrosine kinases, VEGF-R-1 (Flt-1) and VEGF-R- 2 (KDR; whose murine form is known as Flk-1). Activation of these receptors by VEGF triggers the phosphorylation of a multitude of proteins that are active in signal transduction cascades. VEGF gene expression is upregulated by a wide range of stimuli including hypoxia, nitric oxide, estrogen, a variety of growth factors (e.g., FGF-4, PDGF, TNF, TGF-b, EGF, IL-6, IL-1b, #76) and common genetic events associated with the malignant phenotype (loss of tumor suppressor genes such as p53 and activation of oncogenes such as ras, v-src and HER2/neu). Beside major angiogenic properties, VEGF is a potent mitogen for vascular endothelium, inhibits endothelial apoptosis and mobilizes bone marrow-derived endothelial cell precursors. VEGF also mediates the secretion of enzymes involved in the degradation of extracellular matrix, modulates migration, increases vascular permeability, upregulates hexose transport and induces monocyte migration.