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J. Biol. Chem., Vol. 279, Issue 33, 34849-34855, August 13, 2004

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Stretch of the Vascular Wall Induces Smooth Muscle Differentiation by Promoting Actin Polymerization^*

Sebastian Albinsson, Ina Nordström, and Per Hellstrand

From the Division of Molecular and Cellular Physiology, Department of Physiological Sciences, Biomedical Center, Lund University, SE-221 84 Lund, Sweden

Stretch of the vascular wall by the intraluminal blood pressure stimulates protein synthesis and contributes to the maintenance of the smooth muscle contractile phenotype. The expression of most smooth muscle specific genes has been shown to be regulated by serum response factor and stimulated by increased actin polymerization. Hence we hypothesized that stretch-induced differentiation is promoted by actin polymerization. Intact mouse portal veins were cultured under longitudinal stress and compared with unstretched controls. In unstretched veins the rates of synthesis of several proteins associated with the contractile/cytoskeletal system (-actin, calponin, SM22, tropomyosin, and desmin) were dramatically lower than in stretched veins, whereas other proteins (-actin and heat shock proteins) were synthesized at similar rates. The cytoskeletal proteins -actin and vimentin were weakly stretch-sensitive. Inhibition of Rho-associated kinase by culture of stretched veins with Y-27632 produced similar but weaker effects compared with the absence of mechanical stress. Induction of actin polymerization by jasplakinolide increased SM22 synthesis in unstretched veins to the level in stretched veins. Stretch stimulated Rho activity and phosphorylation of the actin-severing protein cofilin-2, although both effects were slow in onset (Rho-GTP, >15 min; cofilin-P, >1 h). Cofilin-2 phosphorylation of stretched veins was inhibited by Y-27632. The F/G-actin ratio after 24 h of culture was significantly greater in stretched than in unstretched veins, as shown by both ultracentrifugation and confocal imaging with phalloidin/DNase I labeling. The results show that stretch of the vascular wall stimulates increased actin polymerization, activating synthesis of smooth muscle-specific proteins. The effect is partially, but probably not completely, mediated via Rho-associated kinase and cofilin downstream of Rho.

Received for publication, March 26, 2004 , and in revised form, May 17, 2004.

^* This work was supported by Swedish Science Council Grant 71X-28 and the Swedish Heart-Lung Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Molecular and Cellular Physiology, BMC F12, SE-221 84 Lund, Sweden. Tel.: 46-46-222-9585; Fax: 46-46-222-4546; E-mail: Per.Hellstrand{at}mphy.lu.

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