FGF-1-DEPENDENT PROLIFERATIVE AND MIGRATORY RESPONSES ARE IMPAIRED INSENESCENT HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS AND CORRELATE WITH THE INABILITY TO SIGNAL TYROSINE PHOSPHORYLATION OF FIBROBLAST GROWTH-FACTOR RECEPTOR-1 SUBSTRATES

Senescent cells do not proliferate in response to exogenous growth fac tors, yet the number and affinity of growth factor receptors on the ce ll surface appear to be similar to presenescent cell populations. To d etermine whether a defect in receptor signaling exists, we analyzed hu man umbilical vein endothelial cells (HUVEC) since HUVEC growth is abs olutely dependent upon the presence of FGF. We report that in both pre senescent and senescent HUVEC populations, FGF-1 induces the expressio n of cell cycle-specific genes, suggesting that functional FGF recepto r (FGFR) may exist on the surface of these cells. However, the tyrosin e phosphorylation of FGFR-1 substrates, Src and cortactin, is impaired in senescent HUVEC, and only the presenescent cell populations exhibi t a FGF-1-dependent Src tyrosine kinase activity. Moreover, we demonst rate that senescent HUVEC are unable to migrate in response to FGF-1, and these data correlate with an altered organization of focal adhesio n sites. These data suggest that the induction of gene expression is i nsufficient to promote a proliferative or migratory phenotype in senes cent HUVEC and that the attenuation of the FGFR-1 signal transduction pathway may be involved in the inability of senescent HUVEC to prolife rate and/or migrate.