Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy
Year: 2023
Type: article
Abstract: Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, including supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates Notch signaling in aortic SMCs. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of catalytic subunits presenilin (PSEN)-1 or PSEN-2 in elastin aortopathy is not defined. Genetic approaches reveal that endothelial cell-specific Psen1 deletion does not improve elastin aortopathy whereas the deletion of either Psen1 in SMCs or Psen2 globally attenuates Notch pathway and SMC proliferation, mitigating aortic disease. With SMC-specific Psen1 deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. SMC deletion of Psen1 also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Similarly, the pharmacological inhibition of PSEN-1 mitigates SMC accumulation in elastin aortopathy. These findings put forth SMC PSEN-1 as a potential therapeutic target in SVAS.
Source: iScience
Institution: Yale University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,150
Funders: American Heart Association, Children's Heart Foundation, Yale University, Harvard Medical School, National Institutes of Health, Japan Society for the Promotion of Science, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Aging and clonality in atherosclerosis, G2627782755, Coordinated regulation of vascular smooth muscle phenotype by p300, CBP, and TET2, G3734958073, G3907600513, G4276273890, Pericyte angiopoietin2 and neonatal intracranial hemorrhage, Mechanisms of reverse vascular remodeling in pulmonary hypertension, Novel vascular smooth muscle cell progenitors in development and disease, Epigenetic-mediated Notch pathway activation promotes elastin aortopathy
OpenAlex ID: W4389670585