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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2366.)
© 2000 American Heart Association, Inc.

Vascular Biology

Pulsatile Stretch–Induced Extracellular Signal–Regulated Kinase 1/2 Activation in Organ Culture of Rabbit Aorta Involves Reactive Oxygen Species

Stéphanie Lehoux; Bruno Esposito; Régine Merval; Laurent Loufrani; Alain Tedgui

From INSERM U541 and IFR "Circulation," Hôpital Lariboisière, Paris, France.

Correspondence to Dr Alain Tedgui, INSERM U541, 41 Boul de la Chapelle, 75010 Paris, France. E-mail tedgui{at}infobiogen.fr

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 O₂^- 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.

Key Words: mechanical stress • pulsatility • signal transduction • extracellular signal–related kinase • tyrosine kinase

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