Embryologic Origins of Aortopathy: Biomechanical Characterization of Aortic Aneurysms in the NOTCH1 Mutant Model

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PROJECT ABSTRACT Aortic aneurysmal disease is a leading causes of death in the US. Ascending aortic aneurysms (AscAA) are associated with aortic dissection and rupture causing significant morbidity and mortality due to a lack of symptoms and limited non-surgical therapies. AscAA are frequently found with congenital heart defects (CHD), specifically bicuspid aortic valve (BAV) and tetralogy of Fallot (TOF). However, the molecular mechanism of CHD-associated AscAA is poorly understood and there is growing evidence that the mechanism of aneurysm formation and progression is heterogeneous. As such, disease progression and risk of developing an acute aortic event is poorly predicted and subsequent clinical guidelines are inadequate. A better understanding of the aortic biomechanical properties is needed to bridge this knowledge gap, identify disease-specific indicators to guide therapy, and produce more effective therapeutics. Mutations in NOTCH1 have been linked to BAV and TOF and we previously described a novel mouse model in which Notch1 haploinsufficiency is sufficient to cause AscAA. Our previously published data suggests that differentiation defects of vascular smooth muscle cell (SMC)-precursors during development contribute to abnormal SMCs in the Notch1+/- adult aorta predisposing to AscAA and implicating an embryologic origin of CHD-associate aortopathy. We hypothesize that loss of NOTCH1 signaling leads to an abnormal tissue response to hemodynamic stress and results in increased wall stiffness. This in turn leads to an increase in wall strain and risk of aortic dissection. The goal of this project is to further investigate the biomechanical properties of the proximal aortic wall in CHD-associated AscAA. We will test our hypothesis by (1) assessing the effects of loss of Notch1 on smooth muscle cell phenotype in response to injury, (2) assessing the biomechanical properties of the smooth muscle cells within the ascending aortas of NOTCH1 haploinsufficent mice, and(3) assessing the biomechanical properties within the proximal ascending aorta of pediatric TOF patients. Successful completion of these aims will help to bridge the current knowledge gap regarding pathogenesis of CHD-associated AscAA disease, assist in improving clinical guidelines, and create opportunities for new therapeutic targets.