Mechanosensitive smooth muscle cell phenotypic plasticity emerging from a null state and the balance between Rac and Rho

Talwar, Shefali; Kant, Aayush; Xu, Tina; Shenoy, Vivek B.; Assoian, Richard K.

doi:10.1016/j.celrep.2021.109019

Cited by 23 publications

(22 citation statements)

References 54 publications

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“…Collectively, these results lead us to posit that HGPS SMCs exist in a relatively de-differentiated phenotypic state. This idea is further supported by our finding of a reduced average size of HGPS SMCs, as de-differentiated SMCs are smaller than differentiated ones ( 38 , 52 ). A defect in vascular smooth muscle differentiation, in turn, might contribute to ECM remodeling, vascular fibrosis, and the increased stiffness seen in the arteries of HGPS children ( 53 ).…”

Section: Discussionsupporting

confidence: 80%

Progerin mislocalizes myocardin-related transcription factor in Hutchinson–Guilford Progeria syndrome

2022

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Hutchinson-Guilford Progeria Syndrome (HGPS) is a rare genetic disease of premature aging and early death due to cardiovascular disease. The arteries of HGPS children and mice are pathologically stiff, and HGPS mice also display reduced arterial contractility. We recently showed that reduced contractility is an early event in HGPS and linked to an aberrantly low expression of smooth muscle myosin-heavy chain (SM-MHC). Here, we have explored the basis for reduced SM-MHC abundance and asked whether it is a direct effect of progerin expression or a longer-term adaptive response. Myh11, the gene encoding for SM-MHC, is regulated by myocardin-related transcription factors (MRTFs), and we show that HGPS aortas have a reduced MRTF signature. Additionally, smooth muscle cells (SMCs) isolated from HGPS mice display reduced MRTF nuclear localization. Acute progerin expression in WT SMCs phenocopied both the decrease in MRTF nuclear localization and expression of Myh11 seen in HGPS. Interestingly, RNA-mediated depletion of MRTF-A in WT SMCs reproduced the preferential inhibitory effect of progerin on Myh11 mRNA relative to Acta2 mRNA. Our results show that progerin expression acutely disrupts MRTF localization to the nucleus and suggest that the consequent decrease in nuclear coactivator activity can help to explain the reduction in SM-MHC abundance and SMC contractility seen in HGPS.

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Section: Discussionsupporting

confidence: 80%

Progerin mislocalizes myocardin-related transcription factor in Hutchinson–Guilford Progeria syndrome

2022

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“…However, the role of TAZ has not been assessed in many developmental contexts, and in most of the cases the main functions have been associated to YAP. YAP and TAZ can act both redundantly, but also in a specific manner ( Morin-Kensicki et al, 2006 ; Hossain et al, 2007 ; Makita et al, 2008 ; Reginensi et al, 2013 ; Talwar et al, 2021 ), depending on the biological process. An open question is whether YAP and TAZ act together in systems where the robustness needs to be maintained, or whether they have specific attributed roles.…”

Section: The Link Between Morphogenetic Changes and Cell Fatementioning

confidence: 99%

Interplay Between Notch and YAP/TAZ Pathways in the Regulation of Cell Fate During Embryo Development

Engel-Pizcueta

Pujades

2021

Front. Cell Dev. Biol.

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Cells in growing tissues receive both biochemical and physical cues from their microenvironment. Growing evidence has shown that mechanical signals are fundamental regulators of cell behavior. However, how physical properties of the microenvironment are transduced into critical cell behaviors, such as proliferation, progenitor maintenance, or differentiation during development, is still poorly understood. The transcriptional co-activators YAP/TAZ shuttle between the cytoplasm and the nucleus in response to multiple inputs and have emerged as important regulators of tissue growth and regeneration. YAP/TAZ sense and transduce physical cues, such as those from the extracellular matrix or the actomyosin cytoskeleton, to regulate gene expression, thus allowing them to function as gatekeepers of progenitor behavior in several developmental contexts. The Notch pathway is a key signaling pathway that controls binary cell fate decisions through cell–cell communication in a context-dependent manner. Recent reports now suggest that the crosstalk between these two pathways is critical for maintaining the balance between progenitor maintenance and cell differentiation in different tissues. How this crosstalk integrates with morphogenesis and changes in tissue architecture during development is still an open question. Here, we discuss how progenitor cell proliferation, specification, and differentiation are coordinated with morphogenesis to construct a functional organ. We will pay special attention to the interplay between YAP/TAZ and Notch signaling pathways in determining cell fate decisions and discuss whether this represents a general mechanism of regulating cell fate during development. We will focus on research carried out in vertebrate embryos that demonstrate the important roles of mechanical cues in stem cell biology and discuss future challenges.

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“…The ApoE −/− mouse model demonstrated an upregulation of arterial Kalirin in early atherogenesis, and Kalirin loss-of-function via gene deletion, RNAi, and inhibitor treatment showed reduced Rac1 activation, as determined by Rac-GTP levels and reduced SMC proliferation and migration. VSMC differentiation toward a contractile phenotype is dependent on the relative Rac and Rho levels in response to sites of injury and modulation of arterial extracellular matrix (ECM) stiffness [ 122 ]. A large relative increase of Rac in response to initial injury supports VSMC proliferation and de-differentiation, which is a phenotype that is associated with arterial stiffening in atherosclerosis, whereas a subsequent relative increase in Rho may induce VSMCs to a differentiated phenotype during injury resolution.…”

Section: Overview Of Atherosclerosismentioning

confidence: 99%

Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis

Lee

Carley

Butler

et al. 2021

Cells

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Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.

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Mechanosensitive smooth muscle cell phenotypic plasticity emerging from a null state and the balance between Rac and Rho

Cited by 23 publications

References 54 publications

Progerin mislocalizes myocardin-related transcription factor in Hutchinson–Guilford Progeria syndrome

Progerin mislocalizes myocardin-related transcription factor in Hutchinson–Guilford Progeria syndrome

Interplay Between Notch and YAP/TAZ Pathways in the Regulation of Cell Fate During Embryo Development

Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis

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