Absence of dystrophin in mice reduces NO-dependent vascular function and vascular density: total recovery after a treatment with the aminoglycoside gentamicin.
OBJECTIVE
Mutations in the dystrophin gene causing Duchenne's muscular dystrophy (DMD) lead to premature stop codons. In mice lacking dystrophin (mdx mice), a model for DMD, these mutations can be suppressed by aminoglycosides such as gentamicin. Dystrophin plays a role in flow (shear stress)-mediated endothelium-dependent dilation (FMD) in arteries. We investigated the effect of gentamicin on vascular contractile and dilatory functions, vascular structure, and density in mdx mice.


RESULTS
Isolated mice carotid and mesenteric resistance arteries were mounted in arteriographs allowing continuous diameter measurements. Mdx mice showed lower nitric oxide (NO)-dependent FMD and endothelial NO synthase (eNOS) expression as well as decreased vascular density in gracilis and cardiac muscles compared with control mice. Treatment with gentamycin restored these parameters. In contrast, smooth muscle-dependent contractions as well as endothelium-dependent or -independent dilation were not affected by dystrophin deficiency or by gentamicin treatment.


CONCLUSIONS
Dystrophin deficiency induces a selective defect in flow-dependent mechanotransduction, thus attenuating FMD and eNOS expression, and may contribute to low arteriolar density. These findings open important perspectives regarding the mechanism involved in the pathophysiology of genetic diseases related to premature stop codons such as DMD.
Loufrani
Laurent
L
Institut National de la Santé et de la Recherche Médicale Unité 541, Paris, France. Laurent.loufrani@wanadoo.fr
Dubroca
Caroline
C
You
Dong
D
Li
Z
Z
Levy
Bernard
B
Paulin
Denise
D
Henrion
Daniel
D
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D018389:Codon, Nonsense; D003331:Coronary Vessels / Q000473:pathology; D016189:Dystrophin / Q000172:deficiency / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005839:Gentamicins / Q000494:pharmacology / Q000627:therapeutic use*; D018056:Hemorheology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D015398:Signal Transduction; D013314:Stress, Mechanical; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014746:Vimentin / Q000172:deficiency / Q000235:genetics
D018389:Codon, Nonsense; D016189:Dystrophin; D005839:Gentamicins; D014662:Vasoconstrictor Agents; D014746:Vimentin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester