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

<jats:p><jats:bold>Background and purpose: </jats:bold> Marfan syndrome, a connective tissue disorder caused by mutations in <jats:italic>FBN1</jats:italic> encoding fibrillin‐1, results in life‐threatening complications in the aorta, but little is known about its effects in resistance vasculature.</jats:p><jats:p><jats:bold>Experimental approach: </jats:bold> Second‐order mesenteric arteries from mice at 3, 6 and 10 months of age (<jats:italic>n</jats:italic>= 30) heterozygous for the <jats:italic>Fbn1</jats:italic> allele encoding a cysteine substitution (<jats:italic>Fbn1</jats:italic><jats:sup>C1039G/+</jats:sup>) were compared with those from age‐matched control littermates.</jats:p><jats:p><jats:bold>Key results: </jats:bold> 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<jats:sub>50</jats:sub>= 5.64 ± 0.11, control pEC<jats:sub>50</jats:sub>= 7.34 ± 0.04) and 10 months (pEC<jats:sub>50</jats:sub>= 5.99 ± 0.07, control pEC<jats:sub>50</jats:sub>= 6.99 ± 0.14). Pretreatment with <jats:italic>N</jats:italic><jats:sub>ω</jats:sub>‐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<jats:sup>−1</jats:sup>) further inhibited vasorelaxation in Marfan vessels to a greater degree compared with control vessels.</jats:p><jats:p><jats:bold>Conclusions and implications: </jats:bold> Pathogenesis of Marfan syndrome in resistance‐sized arteries increases stiffness and impairs vasomotor function.</jats:p>