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JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency
Jui M. Dave, … , Kathleen A. Martin, Daniel M. Greif
Jui M. Dave, … , Kathleen A. Martin, Daniel M. Greif
Published January 6, 2022
Citation Information: J Clin Invest. 2022;132(5):e142338. https://doi.org/10.1172/JCI142338.
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Research Article Vascular biology Article has an altmetric score of 21

JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency

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Abstract

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln–/– mutants. Eln–/– mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln–/– mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.

Authors

Jui M. Dave, Raja Chakraborty, Aglaia Ntokou, Junichi Saito, Fatima Z. Saddouk, Zhonghui Feng, Ashish Misra, George Tellides, Robert K. Riemer, Zsolt Urban, Caroline Kinnear, James Ellis, Seema Mital, Robert Mecham, Kathleen A. Martin, Daniel M. Greif

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Figure 1

Upregulation of NOTCH3 pathway in human and mouse elastin mutants.

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Upregulation of NOTCH3 pathway in human and mouse elastin mutants.
(A) S...
(A) Schematic of the NOTCH3 pathway. Upon binding ligand (JAG or Delta-like ligand [DLL]) expressed by a neighboring cell, the transmembrane NOTCH full-length receptor is cleaved by tumor necrosis factor-α–converting enzyme (TACE), producing an intermediate form that remains membrane bound but lacks the extracellular region. This intermediate form is further cleaved by γ-secretase to release the NOTCH intracellular domain (NICD), which translocates to the nucleus, forms a complex with transcription factor CSL and coactivator Mastermind-like (MAML), and induces expression of target genes (e.g., HEY and HES family members). (B–D) haSMCs were treated with scrambled (Scr) or ELN-specific siRNA (siELN), and lysates were analyzed. In B, histogram depicts levels of indicated transcripts relative to 18S rRNA in lysates as assessed by qRT-PCR and normalized to Scr treatment (n = 3). Western blots probed for ELN, NOTCH3 (full length and intermediate forms), NICD3, HES1, and GAPDH are shown in C, with densitometry of protein bands relative to GAPDH and normalized to Scr in D (n = 3–5). *P < 0.05, **P < 0.01, ****P < 0.0001 vs. Scr by Student’s t test. (E and F) Aortic lysates from WT or Eln–/– mice at P0.5 (2 aortas pooled per genotype for each n) were resolved by Western blotting for ELN, NICD3, HES1, and GAPDH (E), with densitometry of protein bands relative to GAPDH and normalized to WT (F). n = 3 to 6 mice. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT by Student’s t test. (G and H) iPSC-derived SMC progenitors from WBS or nonsyndromic SVAS patients or controls were differentiated into SMCs. Protein levels of ELN, NICD3, HES1, and GAPDH in these iPSC-SMCs were assessed by Western blotting (G), with densitometric analysis of ELN, HES1, and NICD3 normalized to GAPDH (H) (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA with Tukey’s post hoc test. All data are averages ± SD. Gels and blots for HES1 and GAPDH were run contemporaneously (C, E, and G).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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