Differential contribution of elastin and fibrillin-1 to the cardiovascular phenotype of a double heterozygous Marfan and Williams-Beuren syndrome mouse model

Abstract

Marfan syndrome (MFS) and Williams-Beuren syndrome (WBS) are two genetic diseases of connective tissue caused respectively by mutations in the fibrillin-1 gene (FBN1) and hemizygous loss of the elastin gene (ELN) from an allelic chromosomic deletion. Their respective vascular manifestations are opposed, resulting in thoracic aortic aneurysm in MFS and supravalvular aortic stenosis in WBS. To investigate the interdependence of both essential molecular constituents of elastic fibers, we have generated a double heterozygous mouse model by crossing an MFS female (Fbn1C1041G/+) with a Complete Deletion (CD)-WBS male. We evaluated blood pressure, cardiac and aortic phenotypes, and some physical and cognitive functions in the offspring. Double heterozygous mice (CDMFS) presented the characteristic CD altered behavior. CDMFS mice developed an aneurysm, which progressed over age indistinguishably from MFS mice; CDMFS aortic wall showed a thicker tunica media aorta layer and thinner elastic fibers in accordance with CD mice. The characteristic MFS reduction in vascular smooth muscle cell density is not observed in the CDMFS aorta. CDMFS mice develop the high blood pressure observed in CD animals which does not occur in MFS. Ejection fraction was significantly reduced in MFS, CD, and CDMFS mice compared with WT littermates. Cardiac redox stress markers increased only in CD mice, but not in CDMFS animals. Metalloproteinase-2 protein levels increased only in MFS hearts and partially reduced in CDMFS ones. In conclusion, CDMFS mice exhibited the characteristic phenotypic manifestations of each syndrome, along with the pathological outcomes associated with each elastic fiber component and the respective disease.