Loss of presenilin-1 in smooth muscle cells ameliorates elastin aortopathy

Abstract

AbstractSmooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, such as atherosclerosis, pulmonary hypertension and supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates the Notch pathway in aortic SMCs, resulting in hypermuscularization. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of specific catalytic subunits PSEN-1 or PSEN-2 in elastin aortopathy is not defined. This study utilizes genetic approaches to query the role of PSEN-1/2 in the pathogenesis of elastin mutant mice, which model human SVAS. Although endothelial cell-specificPsen1deletion does not improve elastin aortopathy, deletion of eitherPsen1in SMCs orPsen2globally attenuates Notch downstream gene expression and SMC proliferation, mitigating aortic disease. With SMC-specificPsen1deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. On the background ofPsen1deletion in SMCs, globalPsen2deletion yields additional benefits in regard to elastin aortopathy. Finally, SMC deletion ofPsen1also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Taken together, these findings put forth SMC PSEN-1 as a potential therapeutic target in elastin aortopathy.