Absence of Dystrophin in Mice Reduces NO-Dependent Vascular Function and Vascular Density: Total Recovery After a Treatment with the Aminoglycoside Gentamicin

Abstract

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. Key Words: Duchenne's muscular dystrophy Ⅲ blood vessels Ⅲ flow-mediated dilation Ⅲ endothelium Ⅲ vasodilation Ⅲ arteriolar density F low (shear stress) is the main physiological stimulus that induces the release of vasoactive agents by vascular endothelial cells. 1,2 Flow-mediated dilation (FMD) allows the adaptation of feeding arteries to the metabolic needs of each organ. 1,2 Shear stress mechanotransduction involves extracellular matrix and cell structure proteins. 2 Depolymerization of F-actin into G-actin is rapid on shear stress stimulation, [3][4][5] and the absence of the intermediate filament vimentin markedly lowers FMD. 6 Dystrophin might also play a key role in endothelial cells mechanotransduction in blood vessels, and has been widely shown to be involved in skeletal and cardiac muscle cells mechanotransduction. [7][8][9][10][11] Nevertheless, although dystrophin is present in vascular smooth muscle cells, 12-14 no obvious functional abnormality of the smooth muscle has been found in mice lacking dystrophin (mdx mice). 14 On the other hand, the presence of dystrophin has recently been shown in both mouse and human endothelial cells. 14 Furthermore, endothelium-dependent dilation, in response to shear flow mechanical stimulation, is markedly and selectively attenuated in mdx mice. These findings suggest a role for dystrophin in endothelial mechanotransduction of shear stress. 14 This specific vascular dysfunction might disturb local blood flow supply to target organs and thus requires further investigation in patients with Duchenne's muscular dystrophy (DMD). Indeed, ischemia has been described in skeletal and cardiac muscles in patients suffering dystrophy. [15][16][17] Because shear stress is the main physiological stimulus triggering endothelium-dependent dilation, defects in flow-mechanotransduction might have serious short-term (acute local blood flow control) and long-term (arteries structure, protein expression) consequences. In addition, becaus...

Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient mdx Mice

“…Normalization of NO production attenuated skeletal muscle damage and inflammation without affecting angiogenesis. 34 Recently, Loufrani et al 35 demonstrated that endothelium-dependent vascular smooth muscle relaxation was altered in mdx mice, resulting in attenuation of flow-induced vasodilation. Moreover, the same authors showed that vessel density was decreased in gracilis muscle of mdx mice.…”

Role of the cytoskeleton in flow (shear stress)-induced dilation and remodeling in resistance arteries

“…In mdx mice treated with gentamycin for 2 weeks FMD was equivalent to control 44 . Related compounds with a higher efficiency and less toxicity are actually studied in order to find a treatment of some forms of myopathy 45 .…”

“…Indeed, desmin is most likely involved in the contractility of smooth and skeletal muscle. Defects in the gene encoding for desmin induce rare but severe cardiomyopathies 44 .…”

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

“…Arteries were bathed in a physiological salt solution maintained at 37 1C, pH 7.4 (pO 2 160 mm Hg, pCO 2 37 mm Hg). 30 Wall tension was applied as previously described. 31 In brief, arteries were set to the baseline circumference L 0 , where L 0 ¼0.9L 100 is the internal circumference that the artery would have in vivo when relaxed and under a transmural pressure of 100 mm Hg.…”