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Spontaneous aneurysm development after YAP and TAZ deletion

ABSTRACT: Inadequate adaption to mechanical forces, including an elevated blood pressure, contributes to the development of arterial aneurysms. Recent studies have pointed to a mechano-protective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we created vascular SMC-specific knockouts (KOs) of YAP and TAZ using integrin-alpha8-Cre mice (i8-YT-KO). I8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within two weeks of knockout induction. Loss of YAP expression was also observed in human aortic aneurysms. I8-YT-KO mice developed vascular lesions in other arteries at later times, but the gastrointestinal tract was spared. Aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and inflammatory cells, including macrophages and neutrophils. RNA-sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of vascular myocardin expression, reduced blood pressure, and edema. Mediators in the cGAS-STING pathway, which sparks inflammation in response to double-stranded DNA, were increased in aortic lysates. A sizeable increase of the transcription factor Sox9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring three days after knockout induction, and before the pro-inflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that re-capitulates features of human abdominal aortic aneurysms.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Thomas Jepps

PROVIDER: MSV000091464 | MassIVE | Fri Mar 10 05:58:00 GMT 2023

REPOSITORIES: MassIVE

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Project description:Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (YAP) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of YAP after TCPOBOP treatment in mice and potential role of YAP in CAR-driven proliferative response. Here, we investigated a direct role of YAP in CAR-driven hepatomegaly and hepatocyte proliferation using hepatocyte-specific YAP-KO mice. AAV8-TBG-CRE vector was injected to YAP-floxed mice for achieving hepatocyte-specific YAP deletion followed by TCPOBOP treatment. YAP deletion did not alter protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and UGT1a1). However, YAP deletion substantially reduced TCPOBOP-induced hepatocyte proliferation. TCPOBOP-driven cell cycle activation was disrupted in YAP-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in YAP-KO mice. Microarray analysis revealed that 26% of TCPOBOP‐responsive genes mainly related to proliferation, but not to drug metabolism, were altered by YAP deletion. YAP regulated these proliferation genes via alerting expression of cMyc and FOXM1, two critical transcriptional regulators of CAR-mediated hepatocyte proliferation. Conclusion: Our study revealed an important role of YAP signaling in CAR-driven hepatocyte proliferation; however, CAR-driven induction of drug metabolism genes was independent of YAP. We used microarrays to detail the global programme of gene expression in livers of hepatocyte-specific YAP KO mice following TCPOBOP treatment

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Spontaneous aneurysm development after YAP and TAZ deletion

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