Abstract 11680: Presenilin 1 Deletion in Smooth Muscle Cells Ameliorates Hypermuscularization and Stenosis in Elastin Aortopathy

Abstract

Introduction: Smooth 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 deficiency activates the Notch pathway in aortic SMCs, resulting in hypermuscularization and stenosis. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of specific catalytic subunits presenilin (PSEN)-1 or PSEN-2 in elastin aortopathy is not defined. Psen1 (-/-) mice die shortly after birth with intracranial hemorrhage and bone abnormalities, while Psen2 (-/-) mice are viable. Methods: Western blot and qRT-PCR for PSEN-1 and -2 were performed on human aortic SMCs in culture and wildtype and elastin null aortas at postnatal day (P) 0.5. Genetic deletion of cell type-specific Psen1 and/or global Psen2 was performed on the elastin mutant background. For SMC- or endothelial cell (EC)-specific Psen1 deletion, pregnant dams were injected with tamoxifen at embryonic days 14.5 and 15.5, and elastin mutant pups carrying no Cre, Acta2-CreER T2 , or Cdh5-CreER T2 were analyzed at P0.5. Results: PSEN-1 and -2 are upregulated in aortic SMCs with elastin deficiency in human and mouse. Global Psen2 deletion partially attenuates Notch downstream gene expression and SMC proliferation, mitigating elastin aortopathy while Psen1 deletion in SMCs more significantly inhibits this aortopathy and improves survival of elastin null pups. In contrast, Psen1 deletion in ECs does not improve aortic disease. The combination of global Psen2 deletion and SMC-specific Psen1 deletion has additive rescue effects on elastin aortopathy. In addition, SMC-specific Psen1 deletion rescues hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics human SVAS. Conclusions: Elastin insufficiency in SMCs leads to upregulation of PSEN-1 and -2, which induce Notch signaling and SMC proliferation. Among PSEN subunits and vascular cell types, SMC PSEN-1 plays the major role in elastin aortopathy. Selective inhibition of SMC PSEN-1 may be an attractive therapeutic strategy for SVAS to improve efficacy and mitigate off-target effects of gamma-secretase blockade.