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Vascular smooth muscle–specific YAP/TAZ deletion triggers aneurysm development in mouse aorta

Martínez, Marycarmen Arévalo LU ; Ritsvall, Olivia LU ; Bastrup, Joakim Armstrong ; Celik, Selvi LU ; Jakobsson, Gabriel LU ; Daoud, Fatima LU ; Winqvist, Christopher ; Aspberg, Anders LU orcid ; Rippe, Catarina LU and Maegdefessel, Lars , et al. (2023) In JCI Insight 8(17).
Abstract

Inadequate adaption to mechanical forces, including blood pressure, contributes to development of arterial aneurysms. Recent studies have pointed to a mechanoprotective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we identified reduced expression of YAP1 in human aortic aneurysms. Vascular SMC–specific knockouts (KOs) of YAP/TAZ were thus generated using the integrin α8–Cre (Itga8-Cre) mouse model (i8-YT-KO). i8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within 2 weeks of KO induction and in smaller arteries at later times. The vascular specificity of Itga8-Cre circumvented gastrointestinal effects. Aortic aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of... (More)

Inadequate adaption to mechanical forces, including blood pressure, contributes to development of arterial aneurysms. Recent studies have pointed to a mechanoprotective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we identified reduced expression of YAP1 in human aortic aneurysms. Vascular SMC–specific knockouts (KOs) of YAP/TAZ were thus generated using the integrin α8–Cre (Itga8-Cre) mouse model (i8-YT-KO). i8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within 2 weeks of KO induction and in smaller arteries at later times. The vascular specificity of Itga8-Cre circumvented gastrointestinal effects. Aortic aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and immune cell populations. RNA sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of myocardin expression, reduced blood pressure, and edema. Mediators in the inflammatory cGAS/STING pathway were increased. A sizeable increase in SOX9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring 3 days after KO induction and before the proinflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that recapitulates features of human abdominal aortic aneurysms.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
8
issue
17
article number
e170845
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85170294347
  • pmid:37561588
ISSN
2379-3708
DOI
10.1172/jci.insight.170845
language
English
LU publication?
yes
id
1aa29ce6-e0d1-448c-816b-f035ceaa3654
date added to LUP
2023-10-24 13:26:04
date last changed
2024-11-16 01:01:04
@article{1aa29ce6-e0d1-448c-816b-f035ceaa3654,
  abstract     = {{<p>Inadequate adaption to mechanical forces, including blood pressure, contributes to development of arterial aneurysms. Recent studies have pointed to a mechanoprotective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we identified reduced expression of YAP1 in human aortic aneurysms. Vascular SMC–specific knockouts (KOs) of YAP/TAZ were thus generated using the integrin α8–Cre (Itga8-Cre) mouse model (i8-YT-KO). i8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within 2 weeks of KO induction and in smaller arteries at later times. The vascular specificity of Itga8-Cre circumvented gastrointestinal effects. Aortic aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and immune cell populations. RNA sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of myocardin expression, reduced blood pressure, and edema. Mediators in the inflammatory cGAS/STING pathway were increased. A sizeable increase in SOX9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring 3 days after KO induction and before the proinflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that recapitulates features of human abdominal aortic aneurysms.</p>}},
  author       = {{Martínez, Marycarmen Arévalo and Ritsvall, Olivia and Bastrup, Joakim Armstrong and Celik, Selvi and Jakobsson, Gabriel and Daoud, Fatima and Winqvist, Christopher and Aspberg, Anders and Rippe, Catarina and Maegdefessel, Lars and Schiopu, Alexandru and Jepps, Thomas A. and Holmberg, Johan and Swärd, Karl and Albinsson, Sebastian}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  number       = {{17}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Vascular smooth muscle–specific YAP/TAZ deletion triggers aneurysm development in mouse aorta}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.170845}},
  doi          = {{10.1172/jci.insight.170845}},
  volume       = {{8}},
  year         = {{2023}},
}