# MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm

## TL;DR

This study shows how the MAPK14 protein contributes to the breakdown of vascular smooth muscle cells in abdominal aortic aneurysms by affecting key transcriptional regulators.

## Contribution

The study identifies the MAPK14-driven transcriptional and epigenomic mechanisms promoting vascular smooth muscle cell degeneration in AAA.

## Key findings

- VSMC-Mapk14 knockout mice showed reduced VSMC degeneration markers like endoplasmic reticulum stress and apoptosis.
- Loss of Mapk14 increased contractile VSMC populations and upregulated differentiation genes while suppressing degeneration pathways.
- MAPK14 suppresses SRF/MYOCD/CArG and activates RUNX2 and MRTFA to drive VSMC degeneration.

## Abstract

Vascular smooth muscle cell (VSMC) degeneration is a major mechanism underlying abdominal aortic aneurysm (AAA) formation. However, the upstream signaling pathways that converge on the 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. Compared with wild-type (WT) mice, VSMC-Mapk14 knockout (KO) mice displayed reduced VSMC degeneration, as evidenced by decreased expression of markers of endoplasmic reticulum stress, the unfolded protein response, fibrosis, and apoptosis, after 7 days of Ang II infusion. SnRNA-seq revealed increased VSMCs and reduced fibroblast and immune cell populations in KOs. Reclustering VSMCs revealed an increased proportion of contractile cluster and a reduced proportion of fibrotic cluster in KOs. The VSMC differentiation gene program and upstream pathways were upregulated, whereas 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 expression 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 that the expression of Bcl2, a novel MYOCD/SRF/CArG target, was increased in Mapk14 KO VSMCs. Loss of Mapk14 attenuated MRTFA protein abundance via increased ubiquitin‒proteasome degradation, which was attributed to reduced USP10 protein expression. These findings reveal MAPK14-driven transcriptomic and epigenomic landscapes that promote VSMC degeneration by suppressing SRF/MYOCD/CArG while activating RUNX2 and MRTFA. Our study provides mechanistic insight into MAPK14-mediated VSMC degeneration and provides a basis for MAPK14-targeted therapeutic strategies for AAA.