PRDM16 controls smooth muscle cell fate in atherosclerosis

Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce various cell phenotypes in response to pathologic stimuli^1-3. In atherosclerosis, these phenotypically modulated SMCs regulate plaque composition and influence the risk of major adverse cardiovascular events^4,5. We found that PRDM16, a transcription factor that is genetically associated with cardiovascular disease, is highly expressed in arterial SMCs and downregulated during SMC fate switching in human and mouse atherosclerosis. Loss of Prdm16 in SMCs of mice activates a synthetic modulation program under homeostatic conditions. Single cell analyses show that loss of Prdm16 drives a synthetic program in all SMC populations. Upon exposure to atherogenic stimuli, SMC-selective Prdm16 deficient mice develop SMC-rich, fibroproliferative plaques that contain few foam cells. Acute loss of Prdm16 results in the formation of collagen-rich lesions with thick fibrous caps. Reciprocally, increasing PRDM16 expression in SMCs blocks synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, these results define PRDM16 as a critical determinant of SMC identity and atherosclerotic lesion composition.