Elastin Haploinsufficiency Is Associated With Altered Interstitial Phenotype and Progressive Aortopathy

Supravalvular aortic stenosis (SVAS) [1] is a disease of the cardiovascular system that leads to narrowing of the large arteries in humans. Studies have shown [2] that SVAS is caused by mutations or deletions in the elastin gene resulting in elastin haploinsufficiency. Elastin haploinsufficiency results in systemic hypertension [3], thinner and more numerous elastic lamellae [4], and altered arterial mechanics [5]. Genetically modified elastin deficient mice (ELN+/-) recapitulates the human phenotype including obstructive arterial disease and decreased arterial compliance [1,3]. Elastin deficiency in these mice is associated with changes in the mechanical microenvironment in the vascular wall [6], including enhanced wall thickness, increased smooth muscle cell (SMC) proliferation [7] and stiffening of arteries [8]. However, the molecular mechanisms for these changes are not fully understood. Also from a developmental perspective, no information is available regarding initiation and progression of aortic pathology in ELN+/− mice with time. The objectives of this study were to determine the temporal effects of elastin haploinsufficiency on the functional properties of aortic tissue and the aortic cell phenotype, using the elastin deficient mouse model (ELN+/-). We hypothesized that elastin haploinsufficiency will result in progressive abnormalities in aortic stiffness and dynamic alterations in aortic smooth muscle cell phenotype.