Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm

Pedroza, Albert J; Tashima, Yasushi; Shad, Rohan; Cheng, Paul; Wirka, Robert; Churovich, Samantha; Nakamura, Ken; Yokoyama, Nobu; Cui, Jason Z.; Iosef, Cristiana; Hiesinger, William; Quertermous, Thomas; Fischbein, Michael P.

doi:10.1161/atvbaha.120.314670

Cited by 138 publications

(193 citation statements)

References 57 publications

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“…These finding may also have implications in non-atherosclerotic vasculopathies, such as Marfan and Loeys-Dietz syndromes. Aortopathies such as Marfan’s syndrome have been shown to produce aberrant SMC derived populations that contribute to pathogenesis( 68 ). Contrary to our knockout, which decreases TGFβ signaling, collagen vascular dilated aortopathies are thought to be associated with an increase in TGFβ signaling( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Smad3 Regulates Smooth Muscle Cell Fate and Governs Adverse Remodeling and Calcification of Atherosclerotic Plaque

Cheng

et al. 2020

Preprint

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Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC biology can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD, and is associated with expression of SMAD3 in SMC, but the mechanism by which this gene modifies CAD risk remains poorly understood. SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, positive remodeling, and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 promoted SMC progeny to take on a chondromyocyte fate. These analyses also identified a unique subset of smooth muscle lineage cells that promote remodeling and recruitment of inflammatory cells. This population was marked by uniquely high Mmp3 and Cxcl12 expression, and increased in number after loss of Smad3, thus contributing to higher-risk plaque features. Further investigation of transcriptional mechanisms by which Smad3 mediates TGFβ effects on SMC gene expression provided evidence that it binds in conjunction with Hox and Sox transcription factors in the regulatory region of genes that regulate aortic remodeling and have been linked to human Mendelian aortic aneurysmal diseases. Together, these data suggest that Smad3 expression in SMC inhibits cell state changes that mediate adverse plaque features, including positive remodeling, monocyte recruitment, and vascular calcification.

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Section: Discussionmentioning

confidence: 99%

Smad3 Regulates Smooth Muscle Cell Fate and Governs Adverse Remodeling and Calcification of Atherosclerotic Plaque

Cheng

et al. 2020

Preprint

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“…Experiments in mouse models of TAA associated with fibrillin-1 and fibulin-4 deficiency indicate that defective connection of VSMCs to the elastic laminae is an early event in pathogenesis, which is followed by the downregulation of contractile proteins, upregulation of metalloproteases, and induction of signaling pathways that further promote phenotypic switching and matrix degradation [ 239 , 261 ]. Accordingly, single-cell RNA sequencing (scRNA-Seq) analysis of aortic tissue from a mouse model of MFS shows that although the expression of transcripts coding for contractile proteins such α-SMA, SM-MHC, and Calponin-1 is unchanged at early stages of the disease, the expression of these markers progressively decreases in association with the upregulation of AT 1 R and TGF-β signaling in a specific subset of VSMCs [ 239 , 244 , 354 ].…”

Section: Proposed Model Of Taa Pathogenesis Based On the Function mentioning

confidence: 99%

“…TAA-causing mutation may result in the abnormal assembly, maturation, and function of focal adhesions and actively perturb focal adhesion- and force-dependent signaling in a manner that is not recapitulated by simple loss of attachments to elastin fibers [ 28 , 87 , 91 , 355 ]. Then, dysfunctional signaling downstream of focal adhesions would promote the upregulation of metalloproteinases and other matrix proteins, such as thrombospondin-1, which positively regulate AT 1 R and TGF-β signaling, further exacerbating ECM pathogenic remodeling [ 239 , 244 , 261 , 354 ]. Although the direct potentiation of TGF-β receptor activity by interference with myosin-driven focal adhesion maturation has been shown in vitro, it is not known whether it occurs in vivo [ 152 , 153 ].…”

Section: Proposed Model Of Taa Pathogenesis Based On the Function mentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

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Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

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“…Recent developments in function-transcription approaches, single-cell RNA sequencing, and spatial transcriptomics technologies are giving new opportunities in understanding the biochemical processes at the cellular level. Single-cell RNA sequencing of vascular SMCs has yielded knowledge about their heterogeneity (129), ability to phenotypically modulate in response to various stimuli (130,131), and developmental pathways (132,133). Further, single-cell RNA sequencing following whole cell electrophysiology (Patch-seq) shed light on functional diversity in excitable cell types (134)(135)(136)(137).…”

Section: Discussionmentioning

confidence: 99%

Mechanotransduction in gastrointestinal smooth muscle cells: role of mechanosensitive ion channels

Joshi

Strege

Farrugia

et al. 2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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Mechanosensation, the ability to properly sense mechanical stimuli and transduce them into physiologic responses, is an essential determinant of gastrointestinal (GI) function. Abnormalities in this process result in highly prevalent GI functional and motility disorders. In the GI tract, several cell types sense mechanical forces and transduce them into electrical signals, which elicit specific cellular responses. Some mechanosensitive cells like sensory neurons act as specialized mechanosensitive cells that detect forces and transduce signals into tissue-level physiologic reactions. Non-specialized mechanosensitive cells like smooth muscle cells (SMCs) adjust their function in response to forces. Mechanosensitive cells utilize various mechanoreceptors and mechanotransducers. Mechanoreceptors detect and convert force into electrical and biochemical signals, and mechanotransducers amplify and direct mechanoreceptor responses. Mechanoreceptors and mechanotransducers include ion channels, specialized cytoskeletal proteins, cell junction molecules, and G-protein coupled receptors. SMCs are particularly important due to their role as final effectors for motor function. Myogenic reflex-the ability of smooth muscle to contract in response to stretch rapidly-is a critical smooth muscle function. Such rapid mechanotransduction responses rely on mechano-gated and -sensitive ion channels, which alter their ion pores' opening in response to force, allowing fast electrical and Ca2+ responses. Though GI SMCs express a variety of such ion channels, their identities remain unknown. Recent advancements in electrophysiological, genetic, in vivo imaging, and multi-omic technologies broaden our understanding of how SMC mechano-gated and -sensitive ion channels regulate GI functions. This review discusses GI SMC mechanosensitivity's current developments with a particular emphasis on mechano-gated and -sensitive ion channels.

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Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm

Cited by 138 publications

References 57 publications

Smad3 Regulates Smooth Muscle Cell Fate and Governs Adverse Remodeling and Calcification of Atherosclerotic Plaque

Smad3 Regulates Smooth Muscle Cell Fate and Governs Adverse Remodeling and Calcification of Atherosclerotic Plaque

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Mechanotransduction in gastrointestinal smooth muscle cells: role of mechanosensitive ion channels

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