TY - JOUR

T1 - Vascular smooth muscle-specific YAP/TAZ deletion triggers aneurysm development in mouse aorta

AU - Arévalo Martínez, Marycarmen

AU - Ritsvall, Olivia

AU - Bastrup, Joakim Armstrong

AU - Celik, Selvi

AU - Jakobsson, Gabriel

AU - Daoud, Fatima

AU - Winqvist, Christopher

AU - Aspberg, Anders

AU - Rippe, Catarina

AU - Maegdefessel, Lars

AU - Schiopu, Alexandru

AU - Jepps, Thomas A.

AU - Holmberg, Johan

AU - Swärd, Karl

AU - Albinsson, Sebastian

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Cardiovascular disease

KW - Cell Biology

KW - Hypertension

KW - Vascular Biology

KW - Vasculitis

UR - http://www.scopus.com/inward/record.url?scp=85170294347&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.170845

DO - 10.1172/jci.insight.170845

M3 - Journal article

C2 - 37561588

AN - SCOPUS:85170294347

VL - 8

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 17

M1 - e170845

ER -