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 3

Abdominal aortic aneurysms show disorganized elastin and neointima and adventitial expansion.

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Abdominal aortic aneurysms show disorganized elastin and neointima and a...
(A and B) Sections of the abdominal aorta at 2 and 8 weeks following the first tamoxifen injection. Movat pentachrome, which stains elastin black, collagen yellow, proteoglycans and mucins blue, and smooth muscle red, was used for staining transversally cut cryosections. Low and high magnifications are shown, and the latter are highlighted using boxes in the top row. In controls (Ctrl), medial cells in red were tightly packed between layers of elastin, and the adventitia was bright yellow. In knockout aorta (i8-YT-KO), the lumen circumference was enlarged, elastic lamellae more widely spaced, and there were fewer red medial cells, while blue staining was increased. The adventitia was more cellular. Advanced lesions in i8-YT-KO aortae were characterized by greater enlargement of the lumen diameter, advanced neointima formation (NI) inside the internal elastic lamina (IEL), and further elastin disarray with breaks in the continuity of individual lamellae. (C) Movat pentachrome–stained sections of lesions in the superior mesenteric artery. Neointima formation often encroached on the lumen, and black lamellae were sometimes difficult to identify. (D) Quantification of media thickness and the average number of lamellae in abdominal aorta at 2 weeks (n ≥ 4). ***P < 0.001 by 2-tailed Student’s t test (D).