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

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

doi:10.1172/JCI186146

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Mangum, K. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Li, Q. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Hartmann, K. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Bauer, T. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Wolf, S. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Shadiow, J. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Moon, J. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Barrett, E. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Joshi, A. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Saldana de Jimenez, G. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Rocco, S. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Ahmed, Z. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Bogle, R. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Boyer, K. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Obi, A. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Davis, F. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Chang, L. in: JCI | PubMed | Google Scholar

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Tsoi, L. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Gudjonsson, J. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Damrauer, S. in: JCI | PubMed | Google Scholar |

¹Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, United States of America

²Department of Microbiology and Immunology, University of Michigan, Ann Arbor, United States of America

³Department of Surgery, University of Pennsylvania, Philadelphia, United States of America

⁴Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America

Find articles by Gallagher, K. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI186146.
Copyright © 2025, Mangum et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published March 27, 2025 - Version history

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 (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 (Jmjd3^flox/floxMyh11^CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased EDNRB expression and increased EDNRA expression. Importantly, the Endothelin Receptor A antagonist, BQ-123, reversed HTN after Jmjd3 deletion in vivo. Additionally, single cell RNA-sequencing (scRNA-seq) of human arteries revealed 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.

Version 1 (March 27, 2025): In-Press Preview

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

Article tools

Metrics

Go to

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

Article tools

Metrics

Go to

Sign up for email alerts