Abstract 151: Mineralocorticoid Receptor Antagonism Prevents Vascular Remodeling in Mesenteric Arteries of Mice with type 2 Diabetes

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Abstract

Diabetes induces important structural alterations in large and small arteries. Aldosterone, whose plasma levels are elevated in experimental and human diabetes may actively contribute to this process. We tested the hypothesis that mineralocorticoid receptor antagonism prevents diabetes-associated arterial structural changes. Male, 12-14 weeks old db/db mice, a model of type 2 diabetes, and their non-diabetic counterpart controls were treated with spironolactone (50mg/kg/day) or vehicle (1% ethanol) by gavage for 6 weeks. Structural and mechanical parameters were determined in mesenteric arteries with a pressurized myograph (Danish Myo Tech, Aarhus, Denmark). Spironolactone treatment did not affect blood pressure or fasting glucose levels [(mg/dL) 256.5 ± 31, db/db vs. 104 ± 2.3, control, p<0.05]. Arteries of vehicle-treated db/db mice (dbV) had a smaller internal diameter vs. spironolactone-treated db/db (dbS) and control mice (Con) [(μm) 253.9 ± 24.9 vs. 312.9 ± 10.4 dbS, 338.1 ± 32.6 Con; 120mmHg, p<0.05]. Spironolactone treatment prevented the increase of the thickness of the arterial wall [(μm) 23.2 ± 1.0 dbS vs. 30.4 ± 2.0 dbV, 19.4 ± 1.1 Con, 60 mmHg, p<0.05], of the wall:lumen ratio [0.089 ± 0.003 dbS vs. 0.136 ± 0.013 dbV, 0.069 ± 0.006 Con, 60 mmHg, p<0.05] and of the cross-sectional area [(μm2) 21302.7 ± 1791.7 dbS vs. 30189.1 ± 2314.8 dbV, 19144.4 ± 2331.2 Con, 40 mmHg, p<0.05]. The treatment with spironolactone also improved arterial distensibility in db/db mice [(% mmHg-1) 1.4 ± 0.03 dbS vs. 1.1 ± 0.1 dbV, 1.4 ± 0.02 Con, 40mmHg, p<0.05] and shifted the stress-strain curve to the right, indicating a decrease in vascular stiffness. Picrosirius red staining showed a lower collagen content in arteries from mice dbS [(arbitrary units) 4.1 ± 0.9 dbS vs. 6.9 ± 0.6 dbV, 2.8 ± 0.3 Con; p<0.05]. Preliminary data show that spironolactone treatment prevents augmented vascular c-Src and p38MAPK activation in db/db mice. Our data show that spironolactone treatment prevents inward hypertrophic remodeling in db/db mice, indicating that aldosterone importantly contributes to vascular damage associated with this disease.

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