Marfan Syndrome Decreases Ca ²⁺ Wave Frequency and Vasoconstriction in Murine Mesenteric Resistance Arteries without Changing Underlying Mechanisms

Abstract

Background/Aims: Vascular smooth muscle in Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1, is associated with decreased tonic contraction. As Ca²⁺ waves are tightly associated with vasoconstriction, we hypothesized decreased tonic contraction in Marfan syndrome is due to aberrant Ca²⁺ wave signaling. Methods: Isometric force and intracellular Ca²⁺ were measured from second-order mesenteric arteries from mice heterozygous for the Fbn1 allele encoding a cysteine substitution ( Fbn1^C1039G/+). Results: Phenylephrine concentration-dependently induced tonic contraction associated with sustained repetitive oscillations in intracellular [Ca²⁺] in both control and Marfan vessels, although Marfan vessels displayed significantly decreased Ca²⁺ wave frequency and decreased number of cells exhibiting waves. Inhibition of sarcoplasmic reticulum Ca²⁺ re-uptake by cyclopiazonic acid abolished Ca²⁺ waves, dramatically decreasing tonic contraction. Nifedipine significantly reduced Ca²⁺ wave frequency and tonic contraction, while the nifedipine-insensitive component was abolished by SKF-96365. Ca²⁺ waves and tonic contraction were abolished by 2-aminoethoxydiphenylborate, but were unaffected by ryanodine or tetracaine. Conclusion: Phenylephrine-induced Ca²⁺ waves underlie tonic contraction in resistance-sized mesenteric arteries and appear to be produced by repetitive cycles of regenerative Ca²⁺ release from the sarcoplasmic reticulum. Decreased frequency of Ca²⁺ waves in Marfan syndrome appears to be responsible for reduced tonic contraction.