Abstract 807: Marfan Syndrome Impairs Contractility of Smooth Muscle Cells and Modulates Mechanical Properties of both Aorta and Mesenteric Resistance Artery
Introduction: Marfan syndrome, an autosomal-dominant disorder of connective tissue, caused by mutations in the gene encoding fibrillin-1 (FBN1), the principal component of elastic microfibrils. The major clinical manifestations are aortic complications, but the mechanism of pathogenesis remains unclear. Besides, whether the resistance arterial vasculature would be altered has not been studied. We hypothesized that Marfan syndrome would modify the mechanical properties and contractility of smooth muscle cells in both conduit and resistance artery. Methods and
Results: We studied mice heterozygous for the Fbn1 allele encoding a cysteine substitution in FBN1 (Fbn1C1039G/+) (n=60), which is the most common class of mutation in Marfan syndrome. The littermate Fbn1+/+ mice served as control (n=60). Thoracic aorta (TA) and mesenteric artery (MA, 1st branch) from control and Fbn1C1039G/+ mice at the age of 3, 6, 9 and 12 months were studied. From Movat’s histology and confocal microscopy, Fbn1C1039G/+ arteries at 3 months demonstrated fragmentation of elastin fibrials and disarrangement of collagen structure. By 9 months the elastin content in Fbn1C1039G/+ vessels was only 70% of that in the control, and was correlated with the reduced vessel elasticity. In the isometric force measurement, at 3 months of age, the maximal force generated from Fbn1C1039G/+ vessels in phenylephrine (PE)-stimulation was only 60% of that in the control, and the differences were more pronounced with age. At one year, the sensitivity to PE of Fbn1C1039G/+ TA (p=6.28±0.07 vs 7.26±0.07 in control) was significantly decreased. From the smooth muscle cells of Fbn1C1039G/+ artery, the active force generated in PE-stimulation was greatly reduced (3.5±0.6mN vs 8.5±1.1mN in control). Besides, the intracellular calcium ([Ca2+]i) oscillation was lower in amplitude (F/ F0=1.06±0.02) and frequency (λ=0.09±0.01), compared with these parameters in the control (F/F0=1.3±0.07; λ=0.16±0.02).
Conclusions: In Marfan syndrome, organization of elastin and collagen are disrupted in aorta and mesenteric artery, causing an increase in vessel stiffness. Vessel contractility is markedly reduced, which is possibly due to an aberrant regulation of calcium oscillation in the smooth muscle cells.