Vascular smooth muscle–specific YAP/TAZ deletion triggers aneurysm development in mouse aorta
Marycarmen Arévalo Martínez, Olivia Ritsvall, Joakim Armstrong Bastrup, Selvi Celik, Gabriel Jakobsson, Fatima Daoud, Christopher Winqvist, Anders Aspberg, Catarina Rippe, Lars Maegdefessel, Alexandru Schiopu, Thomas A. Jepps, Johan Holmberg, Karl Swärd, Sebastian Albinsson
Marycarmen Arévalo Martínez, Olivia Ritsvall, Joakim Armstrong Bastrup, Selvi Celik, Gabriel Jakobsson, Fatima Daoud, Christopher Winqvist, Anders Aspberg, Catarina Rippe, Lars Maegdefessel, Alexandru Schiopu, Thomas A. Jepps, Johan Holmberg, Karl Swärd, Sebastian Albinsson
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Research Article Cell biology Vascular biology

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

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 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.

Authors

Marycarmen Arévalo Martínez, Olivia Ritsvall, Joakim Armstrong Bastrup, Selvi Celik, Gabriel Jakobsson, Fatima Daoud, Christopher Winqvist, Anders Aspberg, Catarina Rippe, Lars Maegdefessel, Alexandru Schiopu, Thomas A. Jepps, Johan Holmberg, Karl Swärd, Sebastian Albinsson

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Figure 13

Sox9 induction is the earliest detectable change in the i8-YT-KO aorta.

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Sox9 induction is the earliest detectable change in the i8-YT-KO aorta....
This study identified 3 areas of aneurysm pathogenesis in i8-YT-KO mice, involving SOX9 and chondrogenesis, myocardin (Myocd) and contractile differentiation, and STING and inflammation. To examine which comes first, we analyzed mice at 3 (A–C) and 7 days (D and E) following the first injection of tamoxifen. We assayed transcripts relevant for each of the 3 areas of pathogenesis using RT-qPCR. (A and B) Sox9 was the only transcript that was increased at 3 days. A single outlier was identified using the iterative Grubb’s method and excluded. At 3 days, Myocd and Sting1 were unchanged (n = 7) (A), and no difference in Alcian blue staining was seen (B). FC, fold change. (C) Loss of contractility and remodeling of the caudal artery had not yet occurred (n ≥ 4 mice and 6 arteries). (D and E) At 7 days, both Sox9 and Acan were increased (D), while the remainder of the transcripts remained inert (n = 4) and Alcian blue staining had not yet followed suit (E). *P < 0.05; **P < 0.01 by 2-tailed Student’s t test (A, C [right 2 graphs], and D [except Il6, where Mann-Whitney was used]) or 2-way ANOVA with Bonferroni’s post hoc test (C, left graph).