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