Pulsatile stretch-induced extracellular signal-regulated kinase 1/2 activation in organ culture of rabbit aorta involves reactive oxygen species.

Abstract

Increased steady intraluminal pressure in blood vessels activates the extracellular signal-regulated kinase (ERK)1/2 pathway. However, signal transduction of pulsatile stretch has not been elucidated. Using an organ culture model of rabbit aorta, we studied ERK1/2 activation by pulsatility in vessels maintained at 80 mm Hg for 24 hours. ERK1/2 activity was evaluated by in-gel kinase assays and by Western blot. Compared with control aortas without pulsatility, aortas submitted to a pulsatile 10% variation in vessel diameter displayed a significant increase in ERK1/2 activity (207+/-12%, P<0.001), which remained high after removal of the endothelium. Unlike steady overstretch, pulsatile stretch-induced activation of ERK1/2 was not modified by herbimycin A, a Src family tyrosine kinase inhibitor, but was reduced by other tyrosine kinase inhibitors, tyrphostin A48 and genistein (162+/-27% and 144+/-14%, respectively). Conversely, ERK1/2 activity was markedly decreased in pulsatile vessels treated with staurosporine (114+/-18%) although neither of the more specific protein kinase C inhibitors, Ro-31-8220 or Gö-6976, blocked ERK1/2 activation (209+/-24% and 238+/-34%, respectively), whereas staurosporine had no effect on steady overstretch-induced ERK1/2 activation. Pulsatility induced superoxide anion generation, which was prevented by the NADPH oxidase inhibitor diphenyleneiodonium. Furthermore, polyethylene glycol-superoxide dismutase completely abolished ERK1/2 activation by pulsatility (114+/-12%). Finally, ERK1/2 and O(2)(-) levels in freshly isolated vessels were equivalent to the levels found in pulsatile vessels. In conclusion, pulsatile stretch activates ERK1/2 in the arterial wall via pathways different from those induced by steady overstretch. Pulsatility might be considered a physiological stimulus that maintains a certain degree of ERK1/2 activation via oxygen-derived free radical production.

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@article{Lehoux2000PulsatileSE, title={Pulsatile stretch-induced extracellular signal-regulated kinase 1/2 activation in organ culture of rabbit aorta involves reactive oxygen species.}, author={St{\'e}phanie Lehoux and Bruno Esposito and R{\'e}gine Merval and Laurent Loufrani and Alain Tedgui}, journal={Arteriosclerosis, thrombosis, and vascular biology}, year={2000}, volume={20 11}, pages={2366-72} }