Submitted on October 24, 2003
Accepted
on December 28, 2003
Absence of Dystrophin in Mice Reduces NO-Dependent Vascular Function and
Vascular Density: Total Recovery After a Treatment with the Aminoglycoside
Gentamicin
Laurent Loufrani *; Caroline Dubroca ;
Dong You ; Z. Li ; Bernard Levy ; Denise Paulin ; and
Daniel Henrion
From the Institut National de la Santé et de la Recherche Médicale (INSERM)
Unité 541 (L.L., C.D., D.Y., D.H.), Paris, France; the Department of Physiology,
AP-HP-Hôpital Lariboisière (B.L.), Paris, France; and the Laboratoire de
Biologie Moléculaire de la Différentiation (Z.L., D.P.), Paris VII University,
Paris, France.
* To whom correspondence should be addressed. E-mail: Laurent.loufrani@wanadoo.fr.
Objectives--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.
Methods and 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.
Conclusion--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.
Key words: Duchenne’s muscular dystrophy • blood vessels • flow-mediated dilation
• endothelium • vasodilation • arteriolar density
Collections under which this article appears:
Endothelium/vascular
type/nitric oxide