Endothelial receptor tyrosine kinases involved in angiogenesis

D EVELOPMENTAL growth, the remodeling and regeneration of adult tissues as well as solid tumor growth, can only occur accompanied by blood vessel formation. Angioblasts and hemopoietic precursor cells differentiate from the mesoderm and form the blood islands of the yolk sac and the primary vascular system of the embryo (vasculogenesis). The formation of the rest of the vascular tree is thought to occur as a result of vascular sprouting from pre-existing vessels, a process called angiogenesis (9). Endothelial cells can give rise to several types of functionally and morphologically distinct vessels. Upon angiogenic stimuli, endothelial ceils can re-enter the cell cycle, degrade the underlying basement membrane and migrate, forming capillary sprouts that projectinto theperivascular stroma, and again withdraw from the cell cycle and subsequently differentiate to form new vessels that are functionally adapted to their tissue environment. Thus, angiogenesis, concurrent with tissue development and regeneration depends on the tightly controlled processes of endothelial cell proliferation, migration, differentiation, and survival. On the other hand, dysfunction of the endothelial cell regulatory system is a key feature of many diseases. Most importantly, tumor growth and metastasis have been shown to be angiogenesis dependent (9). Key signals regulating cell growth and differentiation are mediated by polypeptide growth factors and their transmembrane receptors, many of which are tyrosine kinases. Several families of receptor tyrosine kinases have been characterized (46). The main currently known growth factors and receptors transducing angiogenic stimuli are schematically shown in Fig. 1. Some of them, such as the receptors for fibroblast growth factors (FGFR), 1 platelet-derived growth factor-BB (PDGFRB), transforming growth factor-ol (epidermal growth factor receptor, EGFR), and hepatocyte growth factor (Met oncoprotein) are widely expressed in many tissues and cell types, whereas others are strictly endothelial cell specific (46). FGFs (for a review see reference 1) have been shown to be mitogenic and chemotactic for cultured endothelial cells. FGFs also stimulate the production of proteases such as col-