Transcriptional control of smooth muscle cell degeneration

Vascular smooth muscle cell (VSMC) degeneration is a major mechanism underlying abdominal aortic aneurysm (AAA) formation. However, the upstream signaling pathways that converge on transcriptional machinery to drive VSMC degeneration remain elusive. Here we integrated single-nucleus (sn) multi-omics, chromatin immunoprecipitation (ChIP)-seq, and wet lab validation to identify transcriptional effectors of VSMC-MAPK14, which we previously reported to promote AAA. VSMC-Mapk14 knockout (KO) mice displayed reduced VSMC degeneration, evidenced by decreased markers of endoplasmic reticulum stress and unfolded protein response, fibrosis, and apoptosis compared to wild type (WT) after 7 days of Ang II infusion. SnRNA-seq revealed increased VSMCs and reduced fibroblast and immune cell populations in KOs. Reclustering VSMCs showed enrichment of the contractile and reduction of fibrotic clusters. VSMC differentiation gene program and upstream pathways were upregulated, while degeneration pathways, including extracellular matrix remodeling, inflammation, and apoptosis, were downregulated in KO VSMCs. snATAC-seq and validation revealed increased serum response factor (SRF) motif activity and expression, but reduced RUNX2 in KO VSMCs. Integrative analysis of snATAC-seq, ChIP-seq, and bulk RNA-seq identified the MYOCD/SRF/CArG triad as the driver of the contractile gene program following Mapk14 loss. We further found Bcl2, a novel MYOCD/SRF/CArG target, was increased in Mapk14 KO VSMCs. Loss of Mapk14 attenuated MRTFA protein via enhanced ubiquitin-proteasome degradation attributable to reduced USP10. These findings reveal MAPK14-driven transcriptomic and epigenomic landscapes that promote VSMC degeneration by activating SRF/MYOCD/CArG while suppressing RUNX and MRTFA. Our study provides mechanistic insight into MAPK14-mediated VSMC degeneration and a basis for MAPK14-targeted therapeutic strategies for AAA.