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 4

JMJD3 regulates vessel tone via endothelin-ERK signaling in vascular SMCs.

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JMJD3 regulates vessel tone via endothelin-ERK signaling in vascular SMC...
(A) Contractility of aortas harvested from Jmjd3fl/flMyh11Cre+ and Jmjd3fl/flMyh11Cre– mice in response to ET-1 (0–10–7 M) and bosentan (10–8–10–7 M). (B) Contractility of mesenteric artery segments harvested from same mice as in A in response to increasing concentrations of ET-1 (0–10–7 M) and bosentan (10–8–10–7 M), Ang II (0–10–5 M), or PE (0-10–6 M). (C) Graph depicting percentage change contractility of aortic rings treated with ET-1 (0–10–7 M) plus or minus bosentan (10–7 M). (D) Quantified gel areas containing cultured mAoSMCs from Jmjd3fl/flTaglnCre mice. Gels treated with ET-1 (1 μM), ET-1 plus bosentan (10 μM), or bosentan alone. Results depicted as percentage of initial gel area at 24 hours after seeding. (E) Representative Western blot of HuAoSMCs unstimulated, treated with ET-1 (1 μM), or ET-1 plus GSKJ4 (50 nM) and then probed for pERK (top) or total ERK (bottom). Blot with representative densitometry results underneath. (F) Representative Western blot of Jmjd3fl/flTaglnCre+ and Jmjd3fl/flTaglnCre– control mAoSMCs unstimulated, treated with ET-1 (1 μM), or ET-1 plus bosentan (10 μm) and then probed for pERK (top) or total ERK (bottom). Blot with representative densitometry results underneath. (G) Representative immunofluorescent staining for pERK in Jmjd3fl/flTaglnCre+ (right) and Jmjd3fl/flTaglnCre– (left) mAoSMCs (up to 4 high powered fields counted per experiment). (H) Representative immunofluorescent staining of endogenous pERK in mAoSMCs transfected with Flag-Jmjd3. Original magnification, ×20 (G and H). Data are represented as mean ± SEM. n = 3 independent experiments; 6 mice were included in each group for contractility experiments. In vitro experiments representative of SMCs from 4–6 mice per group. Two-way ANOVA (A–C) and 2-tailed Student’s t test (D). *P < 0.05; **P < 0.01; ***P < 0.001.