Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Daoud, Fatima LU orcid ; Holmberg, Johan LU ; Winter, Hanna ; Sachs, Nadja ; Maegdefessel, Lars and Albinsson, Sebastian LU (2025) In Journal of Molecular and Cellular Cardiology Plus 14.
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Chondrogenesis, Hippo signaling, Serum response factor, Transdifferentiation, Vascular calcification, Vascular remodeling
in
Journal of Molecular and Cellular Cardiology Plus
volume
14
article number
100487
publisher
Elsevier
external identifiers
  • scopus:105019927034
  • pmid:41246212
DOI
10.1016/j.jmccpl.2025.100487
language
English
LU publication?
yes
id
44a2f494-9184-416c-9b0c-798f09bdd1ea
date added to LUP
2025-12-12 15:17:35
date last changed
2025-12-13 03:00:05
@article{44a2f494-9184-416c-9b0c-798f09bdd1ea,
  abstract     = {{<p>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.</p>}},
  author       = {{Daoud, Fatima and Holmberg, Johan and Winter, Hanna and Sachs, Nadja and Maegdefessel, Lars and Albinsson, Sebastian}},
  keywords     = {{Chondrogenesis; Hippo signaling; Serum response factor; Transdifferentiation; Vascular calcification; Vascular remodeling}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Molecular and Cellular Cardiology Plus}},
  title        = {{YAP/TAZ deletion in vascular smooth muscle cells mirrors atherosclerosis-associated transcriptional programs}},
  url          = {{http://dx.doi.org/10.1016/j.jmccpl.2025.100487}},
  doi          = {{10.1016/j.jmccpl.2025.100487}},
  volume       = {{14}},
  year         = {{2025}},
}