AORTIC SMOOTH MUSCLE REACTIVITY IN FABRY MICE

ROZENFELD P,; FRITZ M,; BRADY R,; CARLOS ALBERTO FOSSATI; RINALDI G,

Estocolmo

Congreso; 6th. International Symposium on Lysosomal Storage Diseases; 2006

Introduction: Fabry disease results in the systemic and progressive deposition of glycosphingolipids, preferentially in vascular endothelium and smooth muscle cells, leading to vessel occlusion and ischemia. Previous reports demonstrated an increased endothelium-mediated vascular reactivity in Fabry disease. We propose to use the Fabry disease murine model to study the pathophysiology of the vasculopathy in Fabry disease. The aim of this work was to study the aortic reactivity of vessels from Fabry mice (F), in comparison with the wild type mice (WT). Methods: Contraction forces (in milligrams of force per milligram of tissue, mgF/mgT) of aortic rings from F and WT were measured after exposure to either 80 mM KCl or 1 µM norepinephrine (NE). The relaxant agents acethylcholine (Ach) and sodium nitroprusside (SNP) were added to the bath on the top of the agonist-induced contraction, and the relaxation was expressed as a percent of that contraction. Results: Aortic rings from F developed a higher contractile force than WT in [K+]= 80 mM (1526 ± 169 vs. 1083 ± 117 mgF/mgT, P<0.05); and with NE (1412 ± 119 vs. 1174 ± 141 mgF/mgT, NS). After the addition of Ach, the early relaxation did not differ significantly (F: 37 ± 7% y WT: 22 ± 5%). However, at 15 min after the addition of Ach, the relaxation was persistent in F (37 ± 11%)  but not in WT (11 ± 9%, P< 0.05). The percentage of relaxation with the addition of SNP over NE contraction was lower in F than in WT (101 ± 8 % vs. 147 ± 23 %, P<0.03), and this was also true in the case of KCl contraction (40 ± 2 % vs. 60 ± 5 %, P<0.001). Conclusions: 1) Aortic smooth muscle of F exhibited augmented contractile response upon activation of either voltage-operated or receptor-operated channels, being significant  in the former case. 2) SNP-induced relaxation was significantly decreased in F with respect to WT. 3) Ach-induced relaxation, however, did not differ between both strains of mice, and it was more persistent in F than in WT. This could reflect the existence of additional endothelial mediators, different from NO, that could be of greater importance in F than in WT.