Interestingly, besides activation of the MAPK signaling pathway, a long lasting activation of protein kinase C is required for FGF to exert a full mitogenic response in endothelial cells. A similar mechanism of regulation may exist also for the interaction with the ECM that surrounds the endothelium.The capacity of FGFR to mediate chemotaxis resides in the amino acid stretch of its cytoplasmic tail. The angiogenesis process can be mimicked in vitro by culturing endothelial cells on a layer of or within a D permissive matrix substrate. Under these conditions, endothelial cells invade the substratum and organize capillarylike structures with a hollow lumen possibly via a pdependent signaling pathway. Indeed, a brief exposure to FGF hampers endothelial cellcell junctions whereas a prolonged exposure to the growth factor promotes a slow temporal redistribution of the junctional adhesion proteins, platelet endothelial cell adhesion molecule, vascularendothelial cadherin, and D-Cycloserine plakoglobin.FGF transfectants show an invasive and morphogenetic behavior in vitro.In vivo, they are angiogenic, cause the formation of opportunistic vascular Methscopolamine tumors in nude mice, and induce hemangiomas in the chick embryo. Accordingly, FGF transfection affects the expression of numerous genes implicated in the modulation of cell cycle, differentiation, cell adhesion, and stresssurvival. Some of these genes are similarly modulated in vitro and in vivo by administration of the recombinant growth factor. However, FGF transfectants, although angiogenic in the chorioallantoic membrane assay, show a limited capacity to growth under anchorageindependent conditions, to invade D brin gel, to undergo morphogenesis in vitro, and to induce hemangiomas in the chick embryo. The observed differences between FGF and FGF transfectants may reect differences in the intracellular and M.Both low and high molecular weight FGF isoforms show angiogenic activity. Experimental evidences point to different functions of FGF isoforms in transfected endothelial cells, possibly related to differences in their subcellular localization and release.On this basis, the biological differences observed between FGF and FGF endothelial cell transfectants may reect differences in the intracrine andor autocrine activities of the two growth factors.Accordingly, transfection with a secreted form of FGF leads to altered morphology and increased motility in endothelial cells. Indeed, fgfr null embryos are developmentally retarded and dye during gastrulation, the early embryonic lethality occurring prior to a stage in which the role of FGFR in blood vessel development can be evaluated. However, adenovirusmediated expression of dominantnegative FGFR results in a signicant impairment of blood vessel development and maintenance in mouse embryos cultured in vitro. Fgfr mutation results in a later embryonic lethality characterized by the lack of a functional placenta and limb buds. Fgfrdecient mice are normal during gestation and exhibit bone alterations during postnatal development. In keeping with the expression of FGFR on endothelial cells in vivo, the angiogenic activity of recombinant FGF and FGF proteins has been demonstrated in various experimental models, including the chick embryo CAM. The CAM assay is a wellestablished assay for studying the effects of growth factors on blood vessel growth. In contrast with the potent angiogenic response elicited by exogenous FGF in different in vitro and in vivo models, the role of endogenous FGF in angiogenesis remains uncertain.