Imbalanced synthesis of cyclooxygenase-derived thromboxane A2 and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome

Background and purpose: Thoracic aortic dissection is a life-threatening complication of Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1. We have demonstrated that nitric oxide-mediated endothelial-dependent relaxation is impaired in the thoracic aorta in Marfan syndrome. In the present study, we determined whether the cyclooxygenase ( COX)-pathway is involved in the compromised aortic vasomotor function. Experimental approach: Thoracic aortae from mice at 3, 6 and 9 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1(C1039G/+), 'Marfan', n = 35), were compared with those from age-matched controls (n = 35). Key results: Isometric force measurement revealed that preincubation with indomethacin, a non-specific COX inhibitor, but not valeryl salicylate, a specific COX-1 inhibitor, improved the phenylephrine-induced contractions (at 6 months, EC50 and E-max were increased 4.5-fold and by 45%, respectively) in Marfan aortae. Sensitivity to acetylcholine-induced relaxation was improved 10-fold. Blockade of the thromboxane-endoperoxide receptor by SQ-29548 did not affect phenylephrine-mediated contractions in Marfan aortae, although they did respond to the thromboxane analogue, U46619. From 6 months on, phenylephrine-induced secretion of prostacyclin and thromboxane A(2) in Marfan aortae was 200% and 40%, respectively, of those in controls. Reduced COX-1 expression was detected in Marfan aortae at 3 and 9 months, whilst COX-2 expression was increased from 3 months on. Conclusions and implications: The compromised vasomotor function in Marfan thoracic aortae is associated with an imbalanced synthesis of thromboxane A(2) and prostacyclin resulting from the differential protein expression of COX-1 and COX-2.