Loss of FoxO3a prevents aortic aneurysm formation through maintenance of VSMC homeostasis

Lu, Weiling; Zhou, Yu; Zeng, Shan; Zhong, Lintao; Zhou, Shiju; Song, Hui‐Hua; Ding, Rongming; Zhong, Gaojun; Li, Qingrui; Hu, Yuhua; Wen, Zhongyu; Liao, Qin; Wang, Yalan; Lyu, Lianglliang; Zhong, Yiming; Hu, Gonghua; Liao, Yulin; Dong-yang, Xie; Xie, Jin

doi:10.1038/s41419-021-03659-y

Cited by 28 publications

(21 citation statements)

References 43 publications

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“…18,19 Contractile-to-synthetic phenotypic modulation of SMCs was earlier suggested to associate with both TAA and AAA. 20,21 Recent scRNA-seq and lineage-tracing studies have revealed a broad range of additional phenotypes for SMCs and ECs in vasculature (reviewed in Yap et al, 18 Ricard et al, 19 Grootaert et al, 22 Dejana et al 23 ) and suggested phenotypic switching and clonal expansion of specific cell subtypes in aortic aneurysms. 24,25…”

Section: Cell Phenotypes and Plasticitymentioning

confidence: 99%

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

Jauhiainen

Kiema

Hedman

et al. 2022

ATVB

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Smooth muscle cells and endothelial cells have a remarkable level of plasticity in vascular pathologies. In thoracic and abdominal aortic aneurysms, smooth muscle cells have been suggested to undergo phenotypic switching and to contribute to degradation of the aortic wall structure in response to, for example, inflammatory mediators, dysregulation of growth factor signaling or oxidative stress. Recently, endothelial-to-mesenchymal transition, and a clonal expansion of degradative smooth muscle cells and immune cells, as well as mesenchymal stem–like cells have been suggested to contribute to the progression of aortic aneurysms. What are the factors driving the aortic cell phenotype changes and how vascular flow, known to affect aortic wall structure and to be altered in aortic aneurysms, could affect aortic cell remodeling? In this review, we summarize the current literature on aortic cell heterogeneity and phenotypic switching in relation to changes in vascular flow and aortic wall structure in aortic aneurysms in clinical samples with special focus on smooth muscle and endothelial cells. The differences between thoracic and abdominal aortic aneurysms are discussed.

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Section: Cell Phenotypes and Plasticitymentioning

confidence: 99%

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

Jauhiainen

Kiema

Hedman

et al. 2022

ATVB

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“…Moreover, five hub genes (FOXO3, DICER1, CCND2, IGF1R, and TNRC6B) were identified by the cytoHubba plugin based on the PPI network. Among them, FOXO3 was reported to promote VSMC phenotypic switching to accelerate aortic aneurysm formation ( Lu et al, 2021 ). DICER1 functioned as a ribonuclease and DICER-dependent miRNAs were important for VSMC development and functioned by regulating proliferation and contractile differentiation ( Albinsson et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Hsa_circ_0031608: A Potential Modulator of VSMC Phenotype in the Rupture of Intracranial Aneurysms

Wang

Luo

Tang

et al. 2022

Front. Mol. Neurosci.

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Background and PurposePhenotypic modulation of vascular smooth muscle cells (VSMCs) plays an important role in the development of intracranial aneurysms (IAs). Growing evidence has demonstrated that circular RNAs (circRNAs) may serve as a potential modulator of VSMC phenotype in various vascular diseases. This study aimed to assess the potential function of circRNAs in the rupture of IAs and VSMC phenotypic modulation.MethodsUsing surgically dissected human ruptured (n = 8) and unruptured (n = 8) IA lesions, differentially expressed circRNAs were screened by transcriptomic sequencing and verified using qRT-PCR. Based on the screened circRNA, we predicted and screened the combined miRNA and downstream mRNAs to construct circRNA-miRNA-mRNA networks. Further in vitro experiments were performed to investigate the relationship between the validated circRNA and the phenotypic switching of VSMCs.ResultsWe found 1,373 differentially expressed genes in ruptured versus unruptured aneurysms. The top five dysregulated circRNAs were selected for qRT-PCR validation. We found hsa_circ_0031608 was both highly expressed in ruptured IAs and pro-inflammatory transformation of VSMCs. Then, a regulatory circRNA-miRNA-mRNA with one circRNA node, six miRNA nodes, and 84 mRNA nodes was constructed. GO analysis and KEGG pathway enrichment analysis were performed on mRNAs in the network. Then, a PPI network was built based on these mRNAs and five hub genes were identified (FOXO3, DICER1, CCND2, IGF1R, and TNRC6B) by the cytoHubba plugin in Cytoscape software. In vitro, overexpression of hsa_circ_0031608 influenced the expression of VSMC phenotypic markers validated by qPCR and Western blotting. Furthermore, hsa_circ_0031608 promoted the migration and proliferation capacity of VSMCs.Conclusionhsa_circ_0031608 regulated the phenotypic modulation of VSMCs and played an important role in the rupture of IAs. The specific mechanism should be further studied and confirmed.

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“…Through AT 1 R, AngII stimulation produces changes in the contractile machinery, constisting in decreased expression of contractiles markers such as αSMA (ACTA2), SM22a (TAGLN), and SMMHC (MYH11) (9,46). As others (41,47), in parallel with vascular remodeling, we observed significant changes in contractile markers expression in aortas under AngII infusion, with downregulation of "vascular smooth muscle contraction" pathway, and ACTA2 expression, but also TAGLN and MYH11 (see raw data). In addition, this phenotypic switch was maintained in time despite the end of AngII stimulation, for the "vascular smooth muscle contraction pathway", and also for αSMA expression, both at mRNA and protein levels (Figures 4B, 5A).…”

Section: Discussionmentioning

confidence: 99%

Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”

Pothen

Verdoy

Mulder

et al. 2022

Front. Cardiovasc. Med.

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BackgroundActivation of the renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of hypertension. Published evidence on a putative “memory effect” of AngII on the vascular components is however scarce.AimTo evaluate the long-term effects of transient exposure to AngII on the mouse heart and the arterial tissue.MethodsBlood pressure, cardiovascular tissue damage and remodeling, and systemic oxidative stress were evaluated in C57/B6/J mice at the end of a 2-week AngII infusion (AngII); 2 and 3 weeks after the interruption of a 2-week AngII treatment (AngII+2W and AngII +3W; so-called “memory” conditions) and control littermate (CTRL). RNAseq profiling of aortic tissues was used to identify potential key regulated genes accounting for legacy effects on the vascular phenotype. RNAseq results were validated by RT-qPCR and immunohistochemistry in a reproduction cohort of mice. Key findings were reproduced in a homotypic cell culture model.ResultsThe 2 weeks AngII infusion induced cardiac hypertrophy and aortic damage that persisted beyond AngII interruption and despite blood pressure normalization, with a sustained vascular expression of ICAM1, infiltration by CD45+ cells, and cell proliferation associated with systemic oxidative stress. RNAseq profiling in aortic tissue identified robust Acta2 downregulation at transcript and protein levels (α-smooth muscle actin) that was maintained beyond interruption of AngII treatment. Among regulators of Acta2 expression, the transcription factor Myocardin (Myocd), exhibited a similar expression pattern. The sustained downregulation of Acta2 and Myocd was associated with an increase in H3K27me3 in nuclei of aortic sections from mice in the “memory” conditions. A sustained downregulation of ACTA2 and MYOCD was reproduced in the cultured human aortic vascular smooth muscle cells upon transient exposure to Ang II.ConclusionA transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting supporting a “memory” effect despite stimulus withdrawal.

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Loss of FoxO3a prevents aortic aneurysm formation through maintenance of VSMC homeostasis

Cited by 28 publications

References 43 publications

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

Hsa_circ_0031608: A Potential Modulator of VSMC Phenotype in the Rupture of Intracranial Aneurysms

Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”

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