FIBROBLAST GROWTH-FACTOR-II INHIBITS ENDOTHELIAL-CELL APOPTOSIS BY BCL-2-DEPENDENT AND INDEPENDENT MECHANISMS

Intact endothelium acts as a sensor and transducer of signals and also provides a nonthrombogenic surface at the blood-vascular wall interfa ce. Hence, mechanisms that maintain the integrity of the endothelium a re of interest in physiological and pathological states. In this study we show that apoptosis induced by growth factor and serum deprivation of endothelial cells occurs at all phases of the cell cycle and can b e blocked by fibroblast growth factor-2 (FGF-2) independently of its m itogenic activity. As the Bcl-2 family of proteins plays a prominent r ole in regulating cell survival, we attempted to identify Bcl-2 homolo gues expressed in endothelial cells. Here we demonstrate that, in addi tion to the previously identified Al, four other members of the Bcl-2 family, Bcl-2, Mcl-1, Bcl-X-L, and Bar, are expressed in endothelial c ells, Of these family members, only Bcl-2 is induced by FGF-2, Overexp ression of Bcl-2, using a retroviral vector, protects endothelial cell s from serum and growth factor deprivation, There is no difference in FGF-2-induced proliferation between Bcl-2-overexpressing cells and tho se transduced with the empty retroviral vector, At early time points B cl-2 is not up-regulated, but FGF-2 still has a protective effect, How ever, FGF-2 protects only adherent endothelial cells but not those tha t are cultured in suspension. The early effect of FGF-2 is dependent o n tyrosine phosphorylation but not on activation of the MAP kinase pat hway. Thus, FGF-2 inhibits endothelial cell apoptosis by Bcl-2-depende nt and independent mechanisms.