Impact of the maternal environment on cardiovascular features of the offspring in a mouse model of Marfan syndrome

Abstract

BackgroundMarfan syndrome (MFS) is a systemic disorder of the connective tissue caused by heterozygous mutations in the FBN1 gene, which encodes fibrillin 1, a glycoprotein that constitutes elastic fibers. MFS does not exhibit sexual dimorphism regarding prevalence; however, it remains unknown whether the paternal or maternal inheritance of the FBN1 mutation affects the cardiovascular pathology of the offspring. In this study, we aimed to determine the impact of the parental origin of the FBN1 mutation on the cardiovascular manifestations of the offspring using the Fbn1C1041G/+ mouse model of MFS. Methods and ResultsFour experimental groups were generated by crossing wild-type (WT) and MFS mice to obtain WT and MFS offspring from either a paternal (MFS-P) or maternal (MFS-M) MFS parent. Cardiovascular phenotyping of offspring was performed from childhood to adulthood (from one to six months of age), including echocardiography, tail-cuff plethysmography, histopathology, and canonical (pSmad2) and non-canonical (pERK) TGF-{beta} signaling activity in the aortic tissue. At one month of age, both WT and MFS offspring from MFS-M presented lower body weight than those from MFS-P. However, with age, MFS-M offspring became persistently and significantly overweight. Both MFS-P and MFS-M offspring exhibited a significantly increased aortic root diameter compared with WT offspring; however, this enlargement appeared earlier in MFS-M than in MFS-P offspring. These parental and age-related differences in aortic root diameter were accompanied by increased canonical and non-canonical TGF-{beta} signaling. The cardiac ejection fraction was reduced at early ages in both WT and MFS offspring from MFS-M compared with MFS-P, with the difference persisting only in MFS-M offspring at adulthood. Systolic blood pressure was initially lower in MFS-M offspring across both genotypes. However, it progressively increased, resulting in elevated levels in both WT and MFS offspring from MFS-M by six months of age. ConclusionOur results indicate the existence of a gestational maternal MFS environmental factor with an early impact on the aorta and heart of MFS offspring. In adulthood, this becomes normalized in the aorta but not in the heart.