p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells

Abstract

Vascular endothelial growth factor (VEGF) is a potent chemotactic agent for endothelial cells. Yet the signalling pathways that modulate the motogenic effects of VEGF in vascular endothelial cells are still ill defined. In the present study, we found in primary cultures of human umbilical vein endothelial cells (HUVEC) that VEGF increased cell migration and induced a marked reorganization of the microfilament network that was characterized by the formation of stress fibers and the recruitment of vinculin to focal adhesions. VEGF also stimulated the mitogen activated protein (MAP) kinases ERK (extracellular signal-regulated kinase) and p38 (stress activated protein kinase-2), but not SAPK1/JNK (stress activated protein kinase-1/c-Jun NH2-terminal kinase). Activation of p38 resulted in activation of MAP kinase activated protein kinase-2/3 and phosphorylation of the F-actin polymerization modulator, heat shock protein 27 (HSP27). Inhibiting the VEGF-induced activation of ERK with PD098059 did not influence actin organization or cell migration but totally inhibited the VEGF-induced incorporation of thymidine into DNA. Inhibition of p38 activity by the specific inhibitor SB203580 led to an inhibition of HSP27 phosphorylation, actin reorganization and cell migration. The results indicate that the p38 pathway conveys the VEGF signal to microfilaments inducing rearrangements of the actin cytoskeleton that regulate cell migration. By modulating cell migration, p38 may thus be an important regulator of angiogenesis.

Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3

“…Thus, we concluded that ERK is essential for DNA synthesis and that p38 MAP kinase is essential for cell migration. The involvement of p38 MAP kinase in the migration of endothelial cells has recently been suggested for VEGF as well [36]. The activation of ERK and p38 MAP kinase in response to S1P was also inhibited by PTX, suggesting that both ERK and p38 MAP kinase may be located downstream of the G i \G o -proteins in S1P signalling.…”

Vascular endothelial growth factor in eye disease

“…Inhibition of p38 MAPK augments VEGFinduced angiogenesis in the chicken chorioallantoic membrane (CAM) assay (Issbrucker et al, 2003;, without an accompanying increase in vascular permeability (Issbrucker et al, 2003). Moreover, p38 MAPK induces phosphorylation of heat-shock protein-27 (HSP27), a molecular chaperone that positively regulates VEGFinduced actin reorganization and migration (McMullen et al, 2005;Rousseau et al, 1997).…”

“…However, VEGFinduced activation of VEGFR2 also activates the serine/threonine protein kinase p38 MAPK (Rousseau et al, 1997). This kinase is an important modulator of the pro-apoptotic process in various cell types, including endothelial cells.…”

Expression profiling of gastric adenocarcinoma using cDNA array

“…18 p38 MAP kinase activation by VEGF mediates actin reorganization and cell migration in human endothelial cells. 19 By modulating cell migration, p38 may thus be an important regulator of angiogenesis.…”