Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy

Junichi Saito; Jui M Dave; Freddy Duarte Lau; Daniel M Greif

doi:10.1016/j.isci.2023.108636

Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy

iScience. 2023 Dec 13;27(1):108636. doi: 10.1016/j.isci.2023.108636. eCollection 2024 Jan 19.

Authors

Junichi Saito^{1

2

3}, Jui M Dave^{1

2

3}, Freddy Duarte Lau^{1

2}, Daniel M Greif^{1

2

3}

Affiliations

¹ Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA.
² Department of Genetics, Yale University, New Haven, CT 06511, USA.
³ Stem Cell Center, Yale University, New Haven, CT 06511, USA.

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.

Keywords: Biological sciences; Natural sciences; Physiology.

Abstract

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