Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling
Kevin D. Mangum, … , Scott M. Damrauer, Katherine A. Gallagher
Kevin D. Mangum, … , Scott M. Damrauer, Katherine A. Gallagher
Published March 27, 2025
Citation Information: J Clin Invest. 2025;135(11):e186146. https://doi.org/10.1172/JCI186146.
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Research Article Cardiology Genetics

Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling

Abstract

Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating SMC function in HTN, we considered Genome Wide Association Studies (GWAS) of blood pressure, focusing on genes encoding epigenetic enzymes, which control SMC fate in cardiovascular disease. Using statistical fine mapping of the KDM6 Jumonji domain-containing protein D3 (JMJD3) locus, we found that rs62059712 is the most likely casual variant, with each major T allele copy associated with a 0.47 mmHg increase in systolic blood pressure. We show that the T allele decreased JMJD3 transcription in SMCs via decreased SP1 binding to the JMJD3 promoter. Using our unique SMC-specific Jmjd3-deficient murine model (Jmjd3fl/flMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased endothelin receptor B (EDNRB) expression and increased endothelin receptor A (EDNRA) expression. Importantly, the EDNRA antagonist BQ-123 reversed HTN after Jmjd3 deletion in vivo. Additionally, single-cell RNA-Seq (scRNA-Seq) of human arteries revealed a strong correlation between JMJD3 and EDNRB in SMCs. Further, JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs increased HTN-induced arterial remodeling. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing targets that may be used in personalized management of HTN.

Authors

Kevin D. Mangum, Qinmengge Li, Katherine Hartmann, Tyler M. Bauer, Sonya J. Wolf, James Shadiow, Jadie Y. Moon, Emily C. Barrett, Amrita D. Joshi, Gabriela Saldana de Jimenez, Zara Ahmed, Rachael Wasikowski, Kylie Boyer, Andrea T. Obi, Frank M. Davis, Lin Chang, Lam C. Tsoi, Johann Gudjonsson, Scott M. Damrauer, Katherine A. Gallagher

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Figure 2

JMJD3 loss in vascular SMCs results in HTN.

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JMJD3 loss in vascular SMCs results in HTN. (A) Schematic depicting expe...
(A) Schematic depicting experiment and breeding strategy for generating inducible SMC-specific Jmjd3-knockout Jmjd3fl/flMyh11CreERT mice. BP obtained by tail cuff for 14 days in WT, heterozygous, and homozygous Jmjd3fl/flMyh11CreERT mice treated with Ang II via osmotic minipumps. (B) SBP, (C) DBP, and (D) MAP are depicted. n = 4–6 mice per genotype/group. (E) HuAoSMCs were treated with Ang II (100 nM) or Ang II and GSKJ4 (50 nM) and then analyzed for pMLC2 and total MLC2 by Western blotting. Blot is representative of n = 3 independent experiments with representative densitometry depicted below. (F) DEGs obtained from RNA-Seq analysis of cultured mAoSMCs isolated from Jmjd3fl/flTaglnCre+ and Jmjd3fl/flTaglnCre– mice with relevant DEGs depicted to right. DEGs depicted met significant threshold of P < 0.05. Results obtained are representative of samples for each genotype submitted in triplicate and obtained from n = 6–8 mice per sample. (G) Volcano plot for upregulated (red) and downregulated (blue) DEGs with fold-change expression depicted on x axis. Locations of Ednrb and Ednra are annotated. (H) Bar graph of GO analysis for top 10 downregulated genes in Jmjd3fl/flTaglnCre+ SMCs from RNA-Seq results. Gene pathways are listed on y axis and number of gene counts for each pathway are listed on x axis. Data are represented as mean ± SEM. n = 3 independent experiments for in vitro studies. Two-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001.