VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAP/ERK and SAPK/JNK signaling

Vascular endothelial growth factor (VEGF), an endothelial cell-specific mit ogen, promotes endothelial cell survival and angiogenesis. We recently show ed that VEGF can support the growth of human dermal microvascular endotheli al cells (HDMEC) and human umbilical vein endothelial cells in serum-free m edium. Reasoning that VEGF might be modulating apoptotic signal transductio n pathways, we examined mechanisms involved in the anti-apoptotic effect of VEGF on starvation- and ceramide-induced apoptosis in HDMEC. We observed t hat VEGF ameliorated the time-dependent increase in apoptosis, as demonstra ted by morphologic observations, TUNEL assay, and DNA fragmentation. On the other hand, basic fibroblast growth factor only partially prevented apopto sis in serum-starved HDMEC; platelet-derived growth factor-BB was completel y ineffective. VEGF activated the phosphorylation of extracellular signal r egulated kinase (ERK)(1) (p44 mitogen-activated protein kinase; MAPK) and E RK2 (p42 MAPK) in a time- and concentration-dependent manner. Both the VEGF -induced activation and its anti-apoptotic effect were prevented by the spe cific MAPK/ERK inhibitor PD98059. The presence of VEGF also inhibited the s ustained activation of stress-activated protein kinase/c-jun-NH2-kinase (SA PK/JNK) caused by serum starvation and ceramide treatment. Activation of th e MAPK pathway together with inhibition of SAPK/JNK activity by VEGF appear s to be a key event in determining whether an endothelial cell survives or undergoes programmed cell death. (C) 1999 Academic Press.