Dysfunction of endothelial and smooth muscle cells in small arteries of a mouse model of Marfan syndrome

Abstract

Background and purpose: Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1, results in life-threatening complications in the aorta, but little is known about its effects in resistance vasculature. Experimental approach: Second-order mesenteric arteries from mice at 3, 6 and 10 months of age (n = 30) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 C1039G/+) were compared with those from age-matched control littermates. Key results: Stress-strain curves indicated that arterial stiffness was increased at 6 and 10 months of age in Marfan vessels. Isometric force measurement revealed that contraction in response to potassium (60 mM)-induced membrane depolarization was decreased by at least 28% in Marfan vessels at all ages, while phenylephrine (3 μM)-induced contraction was reduced by at least 40% from 6 months. Acetylcholine-induced relaxation in Marfan vessels was reduced to 70% and 45% of control values, respectively, at 6 and 10 months. Sensitivity to sodium nitroprusside was reduced at 6 months (pEC 50 = 5.64 ± 0.11, control pEC 50 = 7.34 ± 0.04) and 10 months (pEC 50 = 5.99 ± 0.07, control pEC 50 = 6.99 ± 0.14). Pretreatment with N ω- Nitro-L-arginine methyl ester (200 μM) had no effect on acetylcholine-induced relaxation in Marfan vessels, but reduced vasorelaxation in control vessels to 57% of control values. Addition of indomethacin (10 μM) and catalase (1000 U·mL -1) further inhibited vasorelaxation in Marfan vessels to a greater degree compared with control vessels. Conclusions and implications: Pathogenesis of Marfan syndrome in resistance-sized arteries increases stiffness and impairs vasomotor function. © 2009 The British Pharmacological Society All rights reserved.