# YAP/TAZ deletion in vascular smooth muscle cells mirrors atherosclerosis-associated transcriptional programs

## TL;DR

Deleting YAP/TAZ in vascular smooth muscle cells causes gene changes similar to those seen in atherosclerosis, suggesting they help prevent the disease.

## Contribution

This study shows YAP/TAZ deletion in VSMCs mimics atherosclerosis-related gene programs, identifying them as potential therapeutic targets.

## Key findings

- YAP/TAZ deletion in VSMCs leads to gene expression changes resembling atherosclerosis in mice and humans.
- Loss of YAP/TAZ promotes inflammatory and chondrogenic pathways while reducing muscle contractile functions.
- YAP/TAZ directly represses genes linked to atherogenesis, such as SRF and NEXN.

## Abstract

The transcriptional co-activators YAP (YAP1) and TAZ (WWTR1) are central regulators of vascular smooth muscle cell (VSMC) phenotype and vascular homeostasis. This study investigates the consequences of VSMC-specific YAP/TAZ deletion and its relevance to atherosclerosis. Using bulk and single-cell RNA sequencing data, we demonstrate that gene expression changes following two (2-week YT) and eight weeks (8-week YT) of YAP/TAZ deletion recapitulate key features of murine and human atherosclerosis. Transcriptomic comparisons revealed substantial overlap and concordance between YAP/TAZ-deficient VSMCs and different stages of plaque development, with 8-week YT displaying stronger resemblance to atherosclerotic lesions. Shared differentially expressed genes were enriched for inflammatory mediators, extracellular matrix remodeling factors, and chondrogenic markers. Gene ontology and Reactome pathway enrichment analyses highlighted upregulation of immune-related pathways, extracellular matrix remodeling, and chondrogenic differentiation, accompanied by the downregulation of muscle contractile programs. Integration of ChIP-seq data and promoter motif analyses identified 19 conserved YAP–TEAD target genes that were consistently repressed at both 2-week and 8-week YT. Several of these target genes were also downregulated in atherosclerotic plaques, such as genes involved in cytoskeletal integrity (e.g., SRF, NEXN). Notably, loss of YAP/TAZ induced a phenotypic shift in VSMCs toward chondromyocyte-like and fibromyocyte-like states, analogous to those seen in murine and human atherosclerosis. These findings suggest that YAP/TAZ safeguard VSMC identity by directly repressing pro-inflammatory and osteochondrogenic programs, and that their disruption may contribute to atherogenesis. This positions YAP/TAZ–TEAD axis as a key guardian of vascular homeostasis and a potential therapeutic target for limiting plaque progression.

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