Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

Abstract

Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.

Phosphatidylinositol Inhibits Vascular Endothelial Growth Factor-A– Induced Migration of Human Umbilical Vein Endothelial Cells

“…Previously studies have reported that p38MAPK induces phosphorylation of the heat shock protein-27 (HSP27), a molecular chaperone, and it positively regulates VEGF-induced actin reorganization and migration (7,27). Therefore, we examined the effect of PI on VEGF-A-induced phosphorylation of p38MAPK.…”

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).…”

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

“…For example, microinjection of a neutralizing anti-p38 antibody into NIH3T3 mouse fibroblast during the G 1 phase resulted in cell cycle arrest at the G 1 /S boundary, 53 but p38 has a negative impact on proliferation in endothelial cells. 54 Several mechanisms have been suggested, including phosphorylation of p53 and p21 WAF1/CIP1 , stabilization of the transcriptional repressor HBP1, and reduction in cyclin D stability and transcription. [55][56][57][58][59][60] Among the primary substrates for p38 is the transcription factor ATF2, 61 which is phosphorylated at residues 69 and 71 by p38 in response to wide range of stimuli, resulting in its transcriptional activation of cell cycle regulatory genes such as cyclin A and cyclin D1.…”