A Causative Role for Oxytocin in Pregnancy-Induced Aortic Dissection in Marfan Syndrome Mouse Models. J. P. Habashi1, E. M. Gallo2, N. Huso2, Y. Chen2, D. Bedja2, D. Huso3, H. C. Dietz2,4 1) Pediatrics, Johns Hopkins University, Baltimore, MD; 2) Genetics, Johns Hopkins University, Baltimore, MD; 3) Comparative Medicine, Johns Hopkins University, Baltimore, MD; 4) Howard Hughes Medical Institute.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in fibrillin-1 (FBN1) that includes a strong predisposition for aortic aneurysm and dissection. Studies in both mouse models and people with MFS suggest that excessive TGF signaling in the aortic wall contributes to disease pathogenesis, with particular relevance of the noncanonical activation of extracellular signal-regulated kinase (ERK). Both aortic aneurysm progression and aberrant ERK activation are abrogated with TGF antagonists including the angiotensin II type 1 receptor blocker (ARB) losartan. Pregnant women with MFS show a high risk of aortic dissection in the immediate peripartum period. We hypothesized a mechanistic role for oxytocin, since it peaks at the end of pregnancy, is sustained during lactation and stimulates peripheral tissues through ERK activation. Using the mgR/mgR mouse model of MFS, we demonstrated a 90% incidence of dissection in the 4 weeks following delivery. Simply removing the mothers from their pups on the day of delivery, thereby eliminating lactation-induced oxytocin release, decreased the incidence of death from 90% to 26%. This was associated with a significant decrease in ascending aortic growth over the 7 week period of pregnancy and lactation (1.40 0.15 vs 0.69 0.36 mm/7weeks; respectively, p0.01). Treatment of pregnant mgR/mgR mice with a continuous infusion of a highly specific oxytocin receptor antagonist (ORA; desGly-NH2-d(CH2)5[D-Tyr2,Thr4]OVT), beginning in the 3rd trimester, reduced the incidence of pregnancy-associated aortic dissection from 90% to 6.7%, despite a sustained ability of treated animals to deliver spontaneously and to nurse. Ascending aortic growth was significantly reduced with ORA treatment as compared to placebo-treated pregnant mgR/mgR mice (0.81 0.54 vs. 1.36 0.40 mm/7wks, respectively; p0.01). The risk of aortic dissection is directly proportional to the level of phosphorylated ERK1/2 in the aortic wall, with elevated levels in MFS mice compared to wild-type littermates, a substantial further elevation in the peripartum period, and normalization of levels through either pup removal or treatment with the oxytocin receptor antagonist (p0.05). This therapeutic strategy has the strong potential to modify vascular risk in woman with MFS and perhaps other heritable connective tissue disorders including Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome.
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