Marfan syndrome (MFS), is a rare vascular disease caused by mutations in the fibrillin1 (Fbn1) gene, leading to the development of thoracic aortic aneurysm (TAA) with dissection and rupture. Both sexes are affected, but men experience earlier and more frequent aortic complications, a disparity also observed in mouse models of MFS. Interestingly, mutations in genes coding for the C-type Natriuretic Peptide (CNP) and transforming growth factor 1 beta (TGF-b1) also lead to Marfan-like syndromes and TAA development. These factors are secreted by the aorta and other organs. Our work aims to 1) determine if altered expressions of natriuretic peptides or TGF-b1 in aortic cells and other organs contribute to TAA development and 2) identify whether one of these factors might play a protective role in the aortae of female Fbn1 +/- mice.

Aortic enlargement was assessed via ultrasound imaging. Male and female Fbn1^C1039G/+ (Fbn1 +/-) mice and their littermates Fbn1 +/+ mice were sacrificed at 24 or 52 weeks. Gene expression of CNP and TGF-b1 were analyzed by qRT-PCR in the ascending and aortic arch (Asc. a), in the descending aorta (Desc. a), abdominal aorta (Abdo. a) and in the kidney, liver, spleen, muscle, both atria, and ventricles.

Male Fbn1 +/- mice display aorta enlargement from 10 weeks and females from 34 weeks. When the aneurysm is well established (52-week-old Fbn1 +/- males), ANP and CNP mRNA levels decreased in the Asc. a, and TGF-b1 increased in the Abdo. a. CNP mRNA level increased in the left atrium and ventricles but decreased in the spleen. TGF-b1 expression increased in all organs. To determine if one of these factors could be cardioprotective, we compared 24-week-old Fbn1 +/- and Fbn1 +/+ female mice, normalizing both to their male counterparts (an age when males have aneurysms, but females do not). CNP and TGF-b1 mRNA decreased in female Asc a. Decreased CNP, but increased TGF-b mRNA expressions were measured in other organs of female mice compared to males.

Our findings show that natriuretic peptides and TGF-b1 are differently regulated in the aorta and other organs. Decreased natriuretic peptides and increased TGF-b1 create a pro-aneurysmal environment, suggesting that reduced TGF-b1 in females may protect against aneurysm development in the aorta.