PRDM16 regulates smooth muscle cell identity and atherosclerotic plaque composition
Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, 'synthetic' SMCs-defined by migration, proliferation and extracellular matrix production-accumulate in atherosclerotic lesions and contribute to fibrous cap formation. The mechanisms driving this synthetic transition remain unclear. Here we identify PRDM16, a gene linked to cardiovascular disease, as a critical transcriptional repressor of the synthetic SMC phenotype. PRDM16 expression declined during SMC modulation, and its deletion in mice induced a synthetic program across all SMC subtypes even without pathological stimuli. Under atherogenic conditions, PRDM16 deficiency resulted in the formation of fibroproliferative plaques with more synthetic SMCs and fewer foam cells. Conversely, enforced PRDM16 expression suppressed SMC migration, proliferation and fibrosis. Mechanistically, PRDM16 occupied chromatin and suppressed activating marks at synthetic loci. These findings establish PRDM16 as a gatekeeper of SMC fate and reveal its role in shaping atherosclerotic plaque composition.
Authors
- Clint L. Miller (ORCID: https://orcid.org/0000-0003-4276-3607)
- Gaëlle Auguste (ORCID: https://orcid.org/0000-0003-4900-6959)
- Chenyi Xue (ORCID: https://orcid.org/0000-0002-8829-7659)
- Josephine M. E. Tan (ORCID: https://orcid.org/0000-0003-2534-3029)
- Muredach P. Reilly (ORCID: https://orcid.org/0000-0002-3035-9386)
- Ryan Calhoun
- Angela H. Weller (ORCID: https://orcid.org/0009-0007-3723-9014)
- Hee‐Woong Lim (ORCID: https://orcid.org/0000-0001-8599-1808)
- Lars Mäegdefessel (ORCID: https://orcid.org/0000-0001-5228-2634)
- Patrick Seale (ORCID: https://orcid.org/0000-0001-7119-1615)
- Esther Lutgens (ORCID: https://orcid.org/0000-0002-2609-5744)
- Shirley S.M. Fong (ORCID: https://orcid.org/0000-0001-6410-7606)
- Hanna Winter (ORCID: https://orcid.org/0000-0001-8110-8627)
- Eirlys Barbara
- Karima Drareni
- Lan Cheng (ORCID: https://orcid.org/0000-0002-0572-6148)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Mayo Clinic (US)
- Columbia University Irving Medical Center (US)
- TUM Klinikum (DE)
- Mayo Clinic in Arizona (US)
- German Centre for Cardiovascular Research (DE)
- Amsterdam University Medical Centers (NL)
- University of Virginia (US)
- University of Cincinnati (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1038/s44161-025-00737-8
- Citations
- 4
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 3.75