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Cellular Signalling Dec 2018Vascular smooth muscle cells (VSMCs) are the major cell type in blood vessels. Unlike many other mature cell types in the adult body, VSMC do not terminally... (Review)
Review
Vascular smooth muscle cells (VSMCs) are the major cell type in blood vessels. Unlike many other mature cell types in the adult body, VSMC do not terminally differentiate but retain a remarkable plasticity. Fully differentiated medial VSMCs of mature vessels maintain quiescence and express a range of genes and proteins important for contraction/dilation, which allows them to control systemic and local pressure through the regulation of vascular tone. In response to vascular injury or alterations in local environmental cues, differentiated/contractile VSMCs are capable of switching to a dedifferentiated phenotype characterized by increased proliferation, migration and extracellular matrix synthesis in concert with decreased expression of contractile markers. Imbalanced VSMC plasticity results in maladaptive phenotype alterations that ultimately lead to progression of a variety of VSMC-driven vascular diseases. The nature, extent and consequences of dysregulated VSMC phenotype alterations are diverse, reflecting the numerous environmental cues (e.g. biochemical factors, extracellular matrix components, physical) that prompt VSMC phenotype switching. In spite of decades of efforts to understand cues and processes that normally control VSMC differentiation and their disruption in VSMC-driven disease states, the crucial molecular mechanisms and signalling pathways that shape the VSMC phenotype programme have still not yet been precisely elucidated. In this article we introduce the physiological functions of vascular smooth muscle/VSMCs, outline VSMC-driven cardiovascular diseases and the concept of VSMC phenotype switching, and review molecular mechanisms that play crucial roles in the regulation of VSMC phenotypic plasticity.
Topics: Animals; Cell Differentiation; Cell Plasticity; Cell Proliferation; Cells, Cultured; Epigenesis, Genetic; Extracellular Matrix; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Signal Transduction; Vascular Diseases
PubMed: 30172025
DOI: 10.1016/j.cellsig.2018.08.019 -
Developmental Cell Oct 2022Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and...
Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and urogenital tracts. SMC differ morphologically and functionally at these different anatomical locations, but the molecular underpinnings of the differences remain poorly understood. Here, using deep single-cell RNA sequencing combined with in situ gene and protein expression analysis in four murine organs-heart, aorta, lung, and colon-we identify a molecular basis for high-level differences among vascular, visceral, and airway SMC, as well as more subtle differences between, for example, SMC in elastic and muscular arteries and zonation of elastic artery SMC along the direction of blood flow. Arterial SMC exhibit extensive organotypic heterogeneity, whereas venous SMC are similar across organs. We further identify a specific SMC subtype within the pulmonary vasculature. This comparative SMC cross-organ resource offers insight into SMC subtypes and their specific functions.
Topics: Mice; Animals; Muscle, Smooth, Vascular; Transcriptome; Myocytes, Smooth Muscle; Aorta; Cells, Cultured
PubMed: 36283392
DOI: 10.1016/j.devcel.2022.09.015 -
European Journal of Clinical... Apr 2022Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case of rupture. In addition to dilation, the... (Review)
Review
BACKGROUND
Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case of rupture. In addition to dilation, the aortic layers can separate by a tear within the layers, defined as aortic dissections (AD). Vascular smooth muscle cells (vSMC) are the predominant cell type within the aortic wall and dysregulation of vSMC functions contributes to AA and AD development and progression. However, since the exact underlying mechanism is poorly understood, finding potential therapeutic targets for AA and AD is challenging and surgery remains the only treatment option.
METHODS
In this review, we summarize current knowledge about vSMC functions within the aortic wall and give an overview of how vSMC functions are altered in AA and AD pathogenesis, organized per anatomical location (abdominal or thoracic aorta).
RESULTS
Important functions of vSMC in healthy or diseased conditions are apoptosis, phenotypic switch, extracellular matrix regeneration and degradation, proliferation and contractility. Stressors within the aortic wall, including inflammatory cell infiltration and (epi)genetic changes, modulate vSMC functions and cause disturbance of processes within vSMC, such as changes in TGF-β signalling and regulatory RNA expression.
CONCLUSION
This review underscores a central role of vSMC dysfunction in abdominal and thoracic AA and AD development and progression. Further research focused on vSMC dysfunction in the aortic wall is necessary to find potential targets for noninvasive AA and AD treatment options.
Topics: Aortic Dissection; Animals; Aortic Aneurysm; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 34698377
DOI: 10.1111/eci.13697 -
Annals of Surgery Sep 2022To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs).
OBJECTIVE
To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs).
BACKGROUND
AAAs represent the most common pathological aortic dilation leading to the fatal consequence of aortic rupture. Both immune and structural cells contribute to aortic degeneration, however, gene specific alterations in these cellular subsets are poorly understood.
METHODS
We performed single-cell RNA sequencing (scRNA-seq) analysis of AAAs and control tissues. AAA-related changes were examined by comparing gene expression profiles as well as detailed receptor-ligand interactions. An integrative analysis of scRNA-seq data with large genome-wide association study data was conducted to identify genes critical for AAA development.
RESULTS
Using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing 8 cell lineages. For immune cells, clustering analysis identified 4 T-cell and 5 monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAAs compared to controls. Gene enrichment analysis on immune subsets identified multiple pathways only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, receptor-ligand analysis defined robust interactions between vascular smooth muscle cells and myeloid populations in AAA tissues. Lastly, integrated analysis of scRNA-seq data with genome-wide association study studies determined that vascular smooth muscle cell expression of SORT1 is critical for maintaining normal aortic wall function.
CONCLUSIONS
Here we provide the first comprehensive evaluation of single-cell composition of the abdominal aortic wall and reveal how the gene expression landscape is altered in human AAAs.
Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Genome-Wide Association Study; Humans; Ligands; Myocytes, Smooth Muscle; Transcriptome
PubMed: 35762613
DOI: 10.1097/SLA.0000000000005551 -
American Journal of Physiology. Cell... Mar 2020Rat L6, mouse C2C12, and primary human skeletal muscle cells (HSMCs) are commonly used to study biological processes in skeletal muscle, and experimental data on these... (Comparative Study)
Comparative Study
Rat L6, mouse C2C12, and primary human skeletal muscle cells (HSMCs) are commonly used to study biological processes in skeletal muscle, and experimental data on these models are abundant. However, consistently matched experimental data are scarce, and comparisons between the different cell types and adult tissue are problematic. We hypothesized that metabolic differences between these cellular models may be reflected at the mRNA level. Publicly available data sets were used to profile mRNA levels in myotubes and skeletal muscle tissues. L6, C2C12, and HSMC myotubes were assessed for proliferation, glucose uptake, glycogen synthesis, mitochondrial activity, and substrate oxidation, as well as the response to in vitro contraction. Transcriptomic profiling revealed that mRNA of genes coding for actin and myosin was enriched in C2C12, whereas L6 myotubes had the highest levels of genes encoding glucose transporters and the five complexes of the mitochondrial electron transport chain. Consistently, insulin-stimulated glucose uptake and oxidative capacity were greatest in L6 myotubes. Insulin-induced glycogen synthesis was highest in HSMCs, but C2C12 myotubes had higher baseline glucose oxidation. All models responded to electrical pulse stimulation-induced glucose uptake and gene expression but in a slightly different manner. Our analysis reveals a great degree of heterogeneity in the transcriptomic and metabolic profiles of L6, C2C12, or primary human myotubes. Based on these distinct signatures, we provide recommendations for the appropriate use of these models depending on scientific hypotheses and biological relevance.
Topics: Adult; Animals; Cell Line; Cell Proliferation; Cells, Cultured; Energy Metabolism; Gene Expression Profiling; Humans; Male; Mice; Middle Aged; Muscle Cells; Muscle Fibers, Skeletal; Muscle, Skeletal; Rats; Species Specificity; Transcriptome
PubMed: 31825657
DOI: 10.1152/ajpcell.00540.2019 -
Circulation Jun 2024Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T...
BACKGROUND
Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis.
METHODS
We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis.
RESULTS
SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models.
CONCLUSIONS
Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.
Topics: Animals; Atherosclerosis; Humans; Myocytes, Smooth Muscle; Mice; Muscle, Smooth, Vascular
PubMed: 38686559
DOI: 10.1161/CIRCULATIONAHA.123.067587 -
International Journal of Molecular... Jun 2020Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such... (Review)
Review
Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such as chronic nausea and vomiting. As no cures are currently available, clinical care is limited to symptom management, while the underlying causes of impaired GI motility remain unaddressed. The efficient movement of contents through the GI tract is facilitated by peristalsis. These rhythmic slow waves of GI muscle contraction are mediated by several cell types, including smooth muscle cells, enteric neurons, telocytes, and specialised gut pacemaker cells called interstitial cells of Cajal (ICC). As ICC dysfunction or loss has been implicated in several GI motility disorders, ICC represent a potentially valuable therapeutic target. Due to their availability, murine ICC have been extensively studied at the molecular level using both normal and diseased GI tissue. In contrast, relatively little is known about the biology of human ICC or their involvement in GI disease pathogenesis. Here, we demonstrate human gastric tissue as a source of primary human cells with ICC phenotype. Further characterisation of these cells will provide new insights into human GI biology, with the potential for developing novel therapies to address the fundamental causes of GI dysmotility.
Topics: Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Interstitial Cells of Cajal; Intestine, Small; Myocytes, Smooth Muscle; Peristalsis; Stomach
PubMed: 32630607
DOI: 10.3390/ijms21124540 -
Arteriosclerosis, Thrombosis, and... Mar 2018The vascular system forms as a branching network of endothelial cells that acquire identity as arterial, venous, hemogenic, or lymphatic. Endothelial specification... (Review)
Review
The vascular system forms as a branching network of endothelial cells that acquire identity as arterial, venous, hemogenic, or lymphatic. Endothelial specification depends on gene targets transcribed by Ets domain-containing factors, including Ets variant gene 2 (Etv2), together with the activity of chromatin-remodeling complexes containing Brahma-related gene-1 (Brg1). Once specified and assembled into vessels, mechanisms regulating lumen diameter and axial growth ensure that the structure of the branching vascular network matches the need for perfusion of target tissues. In addition, blood vessels provide important morphogenic cues that guide or direct the development of organs forming around them. As the embryo grows and lumen diameters increase, smooth muscle cells wrap around the nascent vessel walls to provide mechanical strength and vasomotor control of the circulation. Increasing mechanical stretch and wall strain promote smooth muscle cell differentiation via coupling of actin cytoskeletal remodeling to myocardin and serum response factor-dependent transcription. Remodeling of artery walls by developmental signaling pathways reappears in postnatal blood vessels during physiological and pathological adaptation to vessel wall injury, inflammation, or chronic hypoxia. Recent reports providing insights into major steps in vascular development are reviewed here with a particular emphasis on studies that have been recently published in
Topics: Animals; Arteries; Cell Communication; Cell Differentiation; Cell Lineage; Endothelial Cells; Gene Expression Regulation, Developmental; Humans; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Phenotype; Signal Transduction
PubMed: 29467221
DOI: 10.1161/ATVBAHA.118.310223 -
Current Opinion in Pharmacology Jun 2017Under basal conditions, postnatal skeletal muscle displays little cell turnover. With injury, muscle initiates a rapid repair response to reseal damaged membrane,... (Review)
Review
Under basal conditions, postnatal skeletal muscle displays little cell turnover. With injury, muscle initiates a rapid repair response to reseal damaged membrane, reactivating many developmental pathways to facilitate muscle regeneration and prevent tissue loss. Muscle precursor cells become activated accompanied by differentiation and fusion during both muscle growth and regeneration; inter-cellular communication is required for successful completion of these processes. Cellular communication is mediated by lipids, fusogenic membrane proteins, and exosomes. Muscle-derived exosomes carry proteins and micro RNAs as cargo. Secreted factors such as IGF-1, TGFβ, and myostatin are also released by muscle cells providing local signaling cues to modulate muscle fusion and regeneration. Proteins that regulate myoblast fusion also participate in membrane repair and regeneration. Here we will review methods of muscle cell communication focusing on proteins that mediate membrane fusion, exosomes, and autocrine factors.
Topics: Animals; Cell Communication; Cell Membrane; Exosomes; Humans; MicroRNAs; Muscle Cells; Muscle, Skeletal; Phospholipids; Regeneration
PubMed: 28419894
DOI: 10.1016/j.coph.2017.03.008 -
The FEBS Journal Nov 2022Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major... (Review)
Review
Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major class of regulators of skeletal myogenesis. It is well established that infiltrating immune cells at the site of muscle injury secrete cytokines, which play critical roles in the myofibre repair and regeneration process. In the past 10-15 years, skeletal muscle itself has emerged as a prolific producer of cytokines. Much attention in the field has been focused on the endocrine effects of muscle-secreted cytokines (myokines) on metabolic regulation. However, ample evidence suggests that muscle-derived cytokines also regulate myogenic differentiation and muscle regeneration in an autocrine manner. In this review, we survey cytokines that meet two criteria: (a) evidence of expression by muscle cells; (b) evidence demonstrating a myogenic function. Dozens of cytokines representing several major classes make up this group, and together they regulate all steps of the myogenic process. How such a large array of cytokines coordinate their signalling to form a regulatory network is a fascinating, pressing question. Functional studies that can distinguish the source of the cytokines in vivo are also much needed in order to facilitate exploration of their full therapeutic potential.
Topics: Animals; Cell Differentiation; Cytokines; Mammals; Muscle Cells; Muscle Development; Muscle, Skeletal; Regeneration
PubMed: 35073461
DOI: 10.1111/febs.16372