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Cardiovascular Research Jul 2012Smooth muscle cells (SMCs) possess remarkable phenotypic plasticity that allows rapid adaptation to fluctuating environmental cues, including during development and... (Review)
Review
Smooth muscle cells (SMCs) possess remarkable phenotypic plasticity that allows rapid adaptation to fluctuating environmental cues, including during development and progression of vascular diseases such as atherosclerosis. Although much is known regarding factors and mechanisms that control SMC phenotypic plasticity in cultured cells, our knowledge of the mechanisms controlling SMC phenotypic switching in vivo is far from complete. Indeed, the lack of definitive SMC lineage-tracing studies in the context of atherosclerosis, and difficulties in identifying phenotypically modulated SMCs within lesions that have down-regulated typical SMC marker genes, and/or activated expression of markers of alternative cell types including macrophages, raise major questions regarding the contributions of SMCs at all stages of atherogenesis. The goal of this review is to rigorously evaluate the current state of our knowledge regarding possible phenotypes exhibited by SMCs within atherosclerotic lesions and the factors and mechanisms that may control these phenotypic transitions.
Topics: Animals; Atherosclerosis; Cell Differentiation; Epigenesis, Genetic; Humans; Myocytes, Smooth Muscle; Phenotype; Vascular Diseases
PubMed: 22406749
DOI: 10.1093/cvr/cvs115 -
Current Hypertension Reports May 2014The mineralocorticoid receptor (MR) is a key regulator of blood pressure. MR antagonist drugs are used to treat hypertension and heart failure, resulting in decreased... (Review)
Review
The mineralocorticoid receptor (MR) is a key regulator of blood pressure. MR antagonist drugs are used to treat hypertension and heart failure, resulting in decreased mortality by mechanisms that are not completely understood. In addition to the kidney, MR is also expressed in the smooth muscle cells (SMCs) of the vasculature, where it is activated by the hormone aldosterone and affects the expression of genes involved in vascular function at the cellular and systemic levels. Following vascular injury due to mechanical or physiological stresses, vessels undergo remodeling resulting in SMC hypertrophy, migration, and proliferation, as well as vessel fibrosis. Exuberant vascular remodeling is associated with poor outcomes in cardiovascular patients. This review compiles recent findings on the specific role of SMC-MR in the vascular remodeling process. The development and characterization of a SMC-specific MR-knockout mouse has demonstrated a direct role for SMC-MR in vascular remodeling. Additionally, several novel mechanisms contributing to SMC-MR-mediated vascular remodeling have been identified and are reviewed here, including Rho-kinase signaling, placental growth factor signaling through vascular endothelial growth factor type 1 receptor, and galectin signaling.
Topics: Animals; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocytes, Smooth Muscle; Receptors, Mineralocorticoid; Vascular Remodeling; Vascular System Injuries
PubMed: 24633842
DOI: 10.1007/s11906-014-0427-y -
The Journal of Biological Chemistry Dec 2016Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) are in close contact with blood vessels. SMC phenotypes can be altered during pathological vascular...
Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) are in close contact with blood vessels. SMC phenotypes can be altered during pathological vascular remodeling. However, how SMC phenotypes affect EC properties remains largely unknown. In this study, we found that PDGF-BB-induced synthetic SMCs suppressed EC proliferation and migration while exhibiting increased expression of anti-angiogenic factors, such as endostatin, and decreased pro-angiogenic factors, including CXC motif ligand 1 (CXCL1). Cyclopentenyl cytosine (CPEC), a CTP synthase inhibitor that has been reported previously to inhibit SMC proliferation and injury-induced neointima formation, induced SMC redifferentiation. Interestingly, CPEC-conditioned SMC culture medium promoted EC proliferation and migration because of an increase in CXCL1 along with decreased endostatin production in SMCs. Addition of recombinant endostatin protein or blockade of CXCL1 with a neutralizing antibody suppressed the EC proliferation and migration induced by CPEC-conditioned SMC medium. Mechanistically, CPEC functions as a cytosine derivate to stimulate adenosine receptors A1 and A2a, which further activate downstream cAMP and Akt signaling, leading to the phosphorylation of cAMP response element binding protein and, consequently, SMC redifferentiation. These data provided proof of a novel concept that synthetic SMC exhibits an anti-angiogenic SMC phenotype, whereas contractile SMC shows a pro-angiogenic phenotype. CPEC appears to be a potent stimulator for switching the anti-angiogenic SMC phenotype to the pro-angiogenic phenotype, which may be essential for CPEC to accelerate re-endothelialization for vascular repair during injury-induced vascular wall remodeling.
Topics: Animals; Antineoplastic Agents; Aorta; Cell Movement; Cell Proliferation; Cells, Cultured; Coculture Techniques; Culture Media, Conditioned; Cytidine; Endothelium, Vascular; Male; Myocytes, Smooth Muscle; Neointima; Neovascularization, Physiologic; Phenotype; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 27821588
DOI: 10.1074/jbc.M116.741967 -
The European Respiratory Journal Feb 2013Airway smooth muscle cells produce extracellular matrix proteins, which in turn can promote smooth muscle survival, proliferation and migration. Currently available...
Airway smooth muscle cells produce extracellular matrix proteins, which in turn can promote smooth muscle survival, proliferation and migration. Currently available therapies have little effect on airway smooth muscle matrix production and migration. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to decrease migration and matrix production in various cell lines. In this study, we examined the effect of PPAR ligands on human airway smooth muscle (HASM) matrix production and migration. PPAR expression was examined by RT-PCR and Western blotting. Endogenous PPAR activity was examined by transfecting cells with a PPAR response element-luciferase reporter plasmid. We observed that HASM cells express PPARα, β and γ. A six-fold induction of luciferase activity was observed by stimulating cells with a pan-agonist, indicating endogenous PPAR activity. The PPAR ligands ciglitazone, 15-deoxy-Δ12,14-prostaglandin J(2) and WY-14643 decreased migration towards platelet-derived growth factor receptor. This was not mediated by inhibiting Akt phosphorylation or promoting PTEN activity, but partly through cyclooxygenase-2 induction and prostaglandin E(2) production that increased cyclic AMP levels in the cells. All three ligands also caused an inhibition of collagen and fibronectin secretion by cultured smooth muscle cells. We conclude that PPAR ligands decrease HASM migration and matrix production and are, therefore, potentially useful for modulating airway remodelling.
Topics: Adult; Aged; Cell Movement; Cells, Cultured; Dinoprostone; Extracellular Matrix; Female; Fibronectins; Gene Expression Regulation; Humans; Ligands; Male; Middle Aged; Myocytes, Smooth Muscle; Peroxisome Proliferator-Activated Receptors; Phosphoric Monoester Hydrolases; Signal Transduction
PubMed: 22653770
DOI: 10.1183/09031936.00145009 -
American Journal of Physiology. Cell... May 2019Multiple types of Cl channels regulate smooth muscle excitability and contractility in vascular, gastrointestinal, and airway smooth muscle cells. However, little is...
Multiple types of Cl channels regulate smooth muscle excitability and contractility in vascular, gastrointestinal, and airway smooth muscle cells. However, little is known about Cl channels in detrusor smooth muscle (DSM) cells. Here, we used inside-out single channel and whole cell patch-clamp recordings for detailed biophysical and pharmacological characterizations of Cl channels in freshly isolated guinea pig DSM cells. The recorded single Cl channels displayed unique gating with multiple subconductive states, a fully opened single-channel conductance of 164 pS, and a reversal potential of -41.5 mV, which is close to the of -65 mV, confirming preferential permeability to Cl. The Cl channel demonstrated strong voltage dependence of activation (half-maximum of mean open probability, , ~-20 mV) and robust prolonged openings at depolarizing voltages. The channel displayed similar gating when exposed intracellularly to solutions containing Ca-free or 1 mM Ca. In whole cell patch-clamp recordings, macroscopic current demonstrated outward rectification, inhibitions by 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) and niflumic acid, and insensitivity to chlorotoxin. The outward current was reversibly reduced by 94% replacement of extracellular Cl with I, Br, or methanesulfonate (MsO), resulting in anionic permeability sequence: Cl>Br>I>MsO. While intracellular Ca levels (0, 300 nM, and 1 mM) did not affect the amplitude of Cl current and outward rectification, high Ca slowed voltage-step current activation at depolarizing voltages. In conclusion, our data reveal for the first time the presence of a Ca-independent DIDS and niflumic acid-sensitive, voltage-dependent Cl channel in the plasma membrane of DSM cells. This channel may be a key regulator of DSM excitability.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Membrane; Cells, Cultured; Chloride Channels; Guinea Pigs; Male; Myocytes, Smooth Muscle; Niflumic Acid; Urinary Bladder
PubMed: 30566392
DOI: 10.1152/ajpcell.00327.2018 -
ESC Heart Failure Oct 2022Although considerable progress has been made in the diagnosis and treatment of congenital heart disease-associated pulmonary heart hypertension (CHD-PAH), the clinical...
AIMS
Although considerable progress has been made in the diagnosis and treatment of congenital heart disease-associated pulmonary heart hypertension (CHD-PAH), the clinical prognosis and overall survival of patients with CHD-PAH remain poor. Therefore, the molecular pathogenesis of CHD-PAH requires further investigation. The intermediate filament protein synemin (SYN) is reported to modulate phenotypic alterations and varicose vein development, but there is little understanding of its exact functions in CHD-PAH.
METHODS AND RESULTS
SYN expression in the pulmonary arterioles of CHD-PAH patients and shunt-induced PAH rat models was evaluated using immunohistochemistry and western blot. Cell counts and Transwell migration assays were used to assess the effect of SYN on the proliferation and migration capability of human pulmonary smooth muscle cells (hPASMCs). Adeno-associated viruses (AAVs) have been used to suppress SYN expression in the pulmonary arterioles of rats. Such rats were further used to construct a shunt-induced PAH animal model to investigate the function of SYN in PAH and pulmonary vascular remodelling. Compared with the normal control group, SYN expression was found to be clearly up-regulated in the remodelled pulmonary arterioles of CHD-PAH and shunt-induced PAH rat models. In addition, SYN suppression increased the expression of hPASMC contractile-phenotype markers and decreased the expression of synthetic phenotype markers, in contrast to the control group. SYN suppression also dramatically attenuated the proliferation and migration capability of hPASMCs. Conversely, SYN overexpression promoted phenotypic switch, proliferation, and migration of hPASMCs, whereas these effects were notably alleviated by the protein kinase B (AKT) inhibitor MK-2206. Furthermore, we confirmed that SYN suppression mitigated PAH and pulmonary vascular remodelling induced by high blood flow in vivo.
CONCLUSIONS
Our findings indicated that SYN may represent a promising therapeutic target in the treatment of CHD-PAH.
Topics: Animals; Humans; Rats; Heart Defects, Congenital; Hypertension, Pulmonary; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery; Vascular Remodeling
PubMed: 35769011
DOI: 10.1002/ehf2.14048 -
Cell Cycle (Georgetown, Tex.) Jun 2022Reportedly, dysfunction of human pulmonary arterial smooth muscle cells (PASMCs) is associated with the pathogenesis of pulmonary arterial hypertension (PAH). Herein,...
Reportedly, dysfunction of human pulmonary arterial smooth muscle cells (PASMCs) is associated with the pathogenesis of pulmonary arterial hypertension (PAH). Herein, the role of miR-509-5p in hypoxia-induced PASMCs and the underlying mechanism were explored. PASMCs were cultured under both normoxia and hypoxia conditions. Quantitative real-time polymerase-chain reaction (qPCR) was employed for quantifying the expressions of miR-509-5p and DNMT1 mRNA in the serum of PAH patients and PASMCs. MiR-509-5p mimics and inhibitors were then, respectively, transfected into PAMSCs, and CCK-8 and Transwell assays were utilized to detect PASMCs' proliferation and migration. Flow cytometry was executed for evaluating PASMCs' apoptosis. Interrelation between miR-509-5p and DNMT1 was determined utilizing bioinformatics analysis and dual-luciferase reporter assay. Western blot assay was used to detect the expression of DNMT1 or SOD2. MiR-509-5p in serum samples of patients with PAH as well as hypoxia-induced PASMCs was significantly down-regulated, whereas DNMT1 was markedly up-regulated. MiR-509-5p mimics reduces the proliferation and migration of PASMCs, but promotes the apoptosis; conversely, miR-509-5p inhibitors exerted opposite effects. DNMT1 was identified as a target gene of miR-509-5p, and overexpression of DNMT1 reversed the biological functions of miR-509-5p in regulating the phenotypes of PAMSCs. MiR-509-5p up-regulated the expression of SOD2 by down-regulating DNMT1. MiR-509-5p regulates the proliferation, migration and apoptosis of PASMCs, and restoration of miR-509-5p may be a promising strategy to treat PAH.
Topics: Cell Hypoxia; Cell Movement; Cell Proliferation; Humans; MicroRNAs; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery
PubMed: 35244512
DOI: 10.1080/15384101.2022.2044147 -
Circulation Research Mar 2021The developmental origin of vascular smooth muscle cells (VSMCs) has been increasingly recognized as a major determinant for regional susceptibility or resistance to... (Review)
Review
The developmental origin of vascular smooth muscle cells (VSMCs) has been increasingly recognized as a major determinant for regional susceptibility or resistance to vascular diseases. As a human material-based complement to animal models and human primary cultures, patient induced pluripotent stem cell iPSC-derived VSMCs have been leveraged to conduct basic research and develop therapeutic applications in vascular diseases. However, iPSC-VSMCs (induced pluripotent stem cell VSMCs) derived by most existing induction protocols are heterogeneous in developmental origins. In this review, we summarize signaling networks that govern in vivo cell fate decisions and in vitro derivation of distinct VSMC progenitors, as well as key regulators that terminally specify lineage-specific VSMCs. We then highlight the significance of leveraging patient-derived iPSC-VSMCs for vascular disease modeling, drug discovery, and vascular tissue engineering and discuss several obstacles that need to be circumvented to fully unleash the potential of induced pluripotent stem cells for precision vascular medicine.
Topics: Animals; Cell Differentiation; Cellular Reprogramming Techniques; Humans; Induced Pluripotent Stem Cells; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction
PubMed: 33818124
DOI: 10.1161/CIRCRESAHA.120.318049 -
Annual Review of Physiology Feb 2019Maternal cardiovascular changes during pregnancy include an expansion of plasma volume, increased cardiac output, decreased peripheral resistance, and increased... (Review)
Review
Maternal cardiovascular changes during pregnancy include an expansion of plasma volume, increased cardiac output, decreased peripheral resistance, and increased uteroplacental blood flow. These adaptations facilitate the progressive increase in uteroplacental perfusion that is required for normal fetal growth and development, prevent the development of hypertension, and provide a reserve of blood in anticipation of the significant blood loss associated with parturition. Each woman's genotype and phenotype determine her ability to adapt in response to molecular signals that emanate from the fetoplacental unit. Here, we provide an overview of the major hemodynamic and cardiac changes and then consider regional changes in the splanchnic, renal, cerebral, and uterine circulations in terms of endothelial and vascular smooth muscle cell plasticity. Although consideration of gestational disease is beyond the scope of this review, aberrant signaling and/or maternal responsiveness contribute to the etiology of several common gestational diseases such as preeclampsia, intrauterine growth restriction, and gestational diabetes.
Topics: Animals; Cardiovascular System; Cell Plasticity; Endothelium, Vascular; Female; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pregnancy
PubMed: 30742784
DOI: 10.1146/annurev-physiol-020518-114435 -
In Vitro Cellular & Developmental... Apr 2020Bladder dysfunction is one of the most common diseases that occur for a number of reasons and the current treatment modalities do not improve much in its recovery...
Bladder dysfunction is one of the most common diseases that occur for a number of reasons and the current treatment modalities do not improve much in its recovery process. Tissue engineering in the last two decades has given great hope for the treatment of these disorders. In this study, a composite nanofibrous scaffold was fabricated from chitosan, collagen, and polyvinyl-alcohol polymer blend while curcumin incorporated in scaffold fibers. The scaffold supportive functions from smooth muscle cell differentiation were studied when human-induced pluripotent stem cells were cultured on the scaffolds under differentiation medium. Biocompatibility of the fabricated scaffold increased significantly by incorporating curcumin in the scaffold fibers, where protein adsorption, cell attachment, and viability were increased in the nanofiber/curcumin group compared with the other groups. In addition, the expression level of smooth muscle cell-related genes, including alpha-smooth muscle actin (αSMA), smooth muscle 22 alpha (SM-22a), Caldesmon1, and Calponin1in the stem cells upregulated while cultured in the presence of curcumin, but this increase was significantly improved while cells cultured on the nanofibers/curcumin. In addition, αSMA protein in the cells cultured on the nanofibers/curcumin expressed significantly higher than those cells cultured on the nanofibers without curcumin. It can be concluded that smooth muscle cell differentiation of the induced pluripotent stem cells promoted by curcumin and this promotion was synergistically improved while curcumin incorporated in the nanofibers. Graphical abstract.
Topics: Animals; Cell Differentiation; Cell Line; Chitosan; Collagen; Curcumin; Feeder Cells; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; Myocytes, Smooth Muscle; Nanofibers; Polyvinyl Alcohol; Rats
PubMed: 32307668
DOI: 10.1007/s11626-020-00445-6