Flow (shear stress)-induced endothelium-dependent dilation is altered in mice lacking the gene encoding for dystrophin

Background-Dystrophin has a key role in striated muscle mechanotransduction of physical forces. Although cytoskeletal elements play a major role in th e mechanotransduction of pressure and flow in vascular cells, the role of d ystrophin in vascular function has not yet been investigated. Thus, we stud ied endothelial and muscular responses of arteries isolated from mice lacki ng dystrophin (mdx mice). Methods and Results-Carotid and mesenteric resistance arteries 120 mum in d iameter were isolated and mounted in vitro in an arteriograph to control in traluminal pressure and flow. Blood pressure was not affected by the absenc e of dystrophin. Pressure-induced (myogenic), phenylephrine-induced, and KC l-induced forms of tone were unchanged. Flow (shear stress)-induced dilatio n in arteries isolated from mdx mice was decreased by 50% to 60%, whereas d ilation to acetylcholine or sodium nitroprusside was unaffected. N-G-nitro- L-arginine methyl ester-sensitive flow dilation was also decreased in arter ies from mdx mice. Thus, the absence of dystrophin was associated with a de fect in signal transduction of shear stress. Dystrophin was present in vasc ular endothelial and smooth muscle cells, as shown by immunolocalization, a nd localized at the level of the plasma membrane, as seen by confocal micro scopy of perfused isolated arteries. Conclusions-This is the first functional study of arteries lacking the gene for dystrophin. Vascular reactivity was normal, with the exception of now- induced dilation. Thus, dystrophin could play a specific role in shear-stre ss mechanotransduction in arterial endothelial cells. Organ damage in such diseases as Duchenne dystrophy might be aggravated by such a defective arte rial response to flow.