Research ArticleMARFAN SYNDROME

Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome

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Science Translational Medicine  01 May 2019:
Vol. 11, Issue 490, eaat4822
DOI: 10.1126/scitranslmed.aat4822

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Dissecting a risk of Marfan syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder associated with manifestations in multiple organ systems. The aorta is a key site affected by this syndrome, and female patients are at risk for aortic dissection associated with pregnancy and childbirth. Traditionally, this risk has been ascribed to labor-induced stress, but Habashi et al. noted that aortic dissection often occurs relatively late postpartum, prompting them to examine possible additional explanations. Using mouse models of Marfan syndrome, the researchers discovered that oxytocin, the hormone involved in milk letdown, plays a key role in aortic dissection, and identified several potential approaches for preventing this complication.

Abstract

Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which initiates uterine contraction and milk letdown for the duration of lactation through phosphorylation of extracellular signal–regulated kinase (ERK). In a mouse model of MFS that shows highly penetrant postnatal aortic dissection, risk was strongly attenuated by preventing lactation or use of an oxytocin receptor antagonist. Survival correlated inversely with the extent of ERK activation in the aortic wall, and strong protection was observed upon attenuation of ERK phosphorylation using an inhibitor of ERK kinase (MEK) or the U.S. Food and Drug Administration–approved medication hydralazine, offering potential therapeutic strategies for pregnancy-associated vascular catastrophe in the setting of MFS.

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