Human Molecular Genetics Advance Access originally published online on June 15, 2006
Human Molecular Genetics 2006 15(14):2266-2275; doi:10.1093/hmg/ddl151
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Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice
1 Department of Child Development, Faculty of Medical and Pharmaceutical Sciences, 2 Division of Transgenic Technology Center for Animal Resource and Development, and 3 Division of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University Graduate School, Kumamoto 860-0811, Japan, 4 Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan, 5 Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, 6 Centre for Biomedical Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK and 7 Hypertension Division, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
* To whom correspondence should be addressed at: Department of Child Development, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School, 1-1-1 Honjou Kumamoto 860-0811, Japan. Tel: +81 963735197; Fax: +81 963735200; Email: kimusige{at}kaiju.medic.kumamoto-u.ac.jp
Received March 1, 2006; Accepted June 7, 2006
Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal 
-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that -adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of -adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.
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