Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells

The mechanisms responsible for the divergent physiological responses of end othelial cells to vascular endothelial growth factor (VEGF) are incompletel y understood. We hypothesized that VEGF elicits increased endothelial perme ability and cell migration via differential activation of intracellular sig nal transduction pathways. To test this hypothesis, we established a model of VEGF-induced endothelial barrier dysfunction and chemotaxis with bovine pulmonary endothelial cells. We compared the effects of VEGF on transendoth elial electrical resistance (TER), actin cytoskeletal remodeling, and chemo taxis of lung endothelial cells and then evaluated the role of the mitogen- activated protein kinases (MAPKs) p38 and extracellular signal-regulated ki nase (ERK)1/2 in VEGF-mediated endothelial responses. The dose response of pulmonary arterial and lung microvascular endothelial cells to VEGF differe d when barrier regulation and chemotaxis were evaluated. Inhibition of tyro sine kinase, phosphoinositol 3-kinase, or p38 MAPK significantly attenuated VEGF-mediated TER, F-actin remodeling, and chemotaxis. VEGF-mediated decre ased TER was also significantly attenuated by inhibition of ERK1/2 MAPK but not by inhibition of fetal liver kinase-1 (flk-1) or Src kinase. In contra st, VEGF-mediated endothelial migration was not attenuated by ERK1/2 inhibi tion but was abolished by inhibition of either flk-1 or Src kinase. These d ata suggest potential mechanisms by which VEGF may differentially mediate p hysiological responses in vivo.