Heterogeneity of the signal transduction pathways for VEGF-induced MAPKs activation in human vascular endothelial cells

Vascular endothelial growth factor (VEGF) activates ERK and p38 MAPK in end othelial cells (ECs). The present study was aimed to compare its intracellu lar signal transduction pathways between three primary cultures of human EC s including human aortic ECs (HAECs), human umbilical vein ECs (HUVECs), an d human microvascular ECs (HMVECs). VEGF activated ERK and p38 MAPK in all of three ECs. Isoforms of p38 MAPK that were activated by VEGF in HUVECs we re p38-alpha and p38-delta. CF109203X, a specific inhibitor of PKC, markedl y inhibited VEGF-induced activation of ERK and p38 MAPK in HAECs and HUVECs , whereas it exhibited little effect in HMVECs. In contrast, dominant negat ive mutant of Ha-Ras almost completely abrogated VEGF-induced activation of ERK and p38 MAPK in HMVECs. Although dominant negative mutant of Ha-Ras su bstantially inhibited the basal activities of ERK and p38 MAPK, it exhibite d marginal effect on VEGF-induced activation of ERK and p38 MAPK in HUVECs and HAEC5. The activation of Ras by VEGF appeared to be most prominent in H MVECs. These results indicate that intracellular signal transduction pathwa ys for VEGF-induced activation of MAPKs are heterogeneous and vary dependin g on the origin of ECs. (C) 2001 Wiley-Liss, Inc.