MECHANISTIC INTERROGATION OF A GENE-BY-ENVIRONMENT INTERACTION INFORMS THE PATHOGENESIS AND TREATMENT OF MENDELIAN ANEURYSM DISORDERS

Aneurysms are local dilations of an artery that predispose the vessel to sudden rupture. They are often asymptomatic and undiagnosed, resulting in a high mortality rate. Bicuspid aortic valve with distal ascending aortic aneurysm is the most common hereditary aneurysm condition affecting approximately 1-2% of the population. Unlike inherited aneurysm disorders characterized by aortic root aneurysm such as Loeys-Dietz syndrome, Marfan syndrome, and Shprintzen-Goldberg syndrome, the genetic causes of bicuspid aortic valve with ascending aortic aneurysm are poorly understood with heterozygous loss of function mutations in NOTCH1 accounting for a very small number of cases. It is not known whether these familial thoracic aortic aneurysm diseases share common mechanistic causes despite their anatomic differences. We have shown that in a mouse model for Marfan syndrome, calcium channel blocker treatment induces a dramatic distal ascending aortic aneurysm phenotype that is ERK1/2- and angiotensin II type1 receptor (AT1R)-dependent. In an unbiased screen to mechanistically characterize this distal ascending aortic aneurysm phenotype, we carried out RNA-sequencing on Marfan syndrome mouse aortas, applying strict a priori filters to select for transcripts that displayed a change in expression in response to CCBs that was abrogated upon ERK1/2 antagonism and the accompanying phenotypic rescue. The top enriched pathways that emerged from this screen were signaling through the Notch pathway and androgen receptor coregulation. Pharmacological manipulation of Notch signaling in our model revealed that signaling through this pathway is overtly protective, as Notch inhibition further accentuates the ascending aneurysm induced by calcium channel blockers in Marfan syndrome mice. This effect remains ERK1/2- and AT1R-dependent. Further investigation into how Notch achieves its therapeutic effect led us to develop and rigorously test a hypothesis accounting for underlying genetic predisposition, anatomic regional variation in aneurysm sensitivity, the protective influence of Notch, and the exacerbating effects of CCBs that collapses on the expression and activity of the regulator of G-protein signaling (RGS) family of proteins – potent inhibitors of AT1R signaling. Finally, we discovered that our mouse model of distal ascending aortic aneurysm is able to recapitulate the male predominance observed in human bicuspid aortic valve with ascending aortic aneurysm, and that this is mediated by the detrimental effects of androgen signaling and the protective effects of estrogen signaling. The work presented here reveals a potential role for Notch agonists, strategies that promote RGS protein activity, and androgen receptor antagonists as therapies in treatment of bicuspid aortic valve with aneurysm and related familial thoracic aortic aneurysm disorders