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Dysfunction of endothelial and smooth muscle cells in small arteries of a mouse model of Marfan syndrome
Author(s) -
Syyong HT,
Chung AWY,
Yang HHC,
van Breemen C
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00439.x
Subject(s) - marfan syndrome , phenylephrine , medicine , contraction (grammar) , sodium nitroprusside , mesenteric arteries , endocrinology , aorta , vasodilation , acetylcholine , endothelial dysfunction , anatomy , cardiology , nitric oxide , artery , blood pressure
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.