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PubMed1996

ATP activates K and Cl channels via purinoceptor-mediated release of Ca2+ in human coronary artery smooth muscle.

Coronary artery smooth muscle cells express G protein-coupled purinoceptors, and we report here for the first time how receptor activation by extracellular ATP influences cell membrane currents and membrane potential in human cells. ATP (100 microM) stimulated a triphasic change in membrane potential lasting several seconds, which was caused by sequential opening of transient inward and outward conductances. The inward current was carried by Cl- and the outward current by K+, as shown by ion substitution and changes in holding potential. Both currents were independent of the presence of external Ca2+ but were blocked by strong buffering of Ca2+ in the internal solution. The P2u- and P2y-purinoceptor agonists UTP and 2-methylthioadenosine 5'-triphosphate activated similar currents, whereas the P2x-receptor agonist alpha, beta-methyleneadenosine 5'-triphosphate and the P1-receptor agonist adenosine failed to stimulate any whole cell currents. The ATP-activated K+ current was inhibited by iberiotoxin (200 nM), and it was potentiated by the BK channel activator NS-1619 (30 microM). In cell-attached recordings, ATP activated a 230-pS BK channel. In conclusion, ATP acting via P2 purinoceptors stimulated release of Ca2+ from internal stores and transiently activated depolarizing Cl- and hyperpolarizing BK channels in human coronary artery smooth muscle cells.

Adenosine Triphosphate↗
PubMed1991

Flow-dependent stimulation of sodium and cholesterol uptake and cell growth in cultured vascular smooth muscle.

A10 vascular smooth muscle cells were placed in a flow chamber and exposed to the circulation of foetal calf serum at different rates and pressures. Under unidirectional laminar flow, physiological flow rates and pressures had almost no effect on internal sodium content. Indeed, pressure values greater than 150 mmHg were required to observe modest increases in sodium content. Conversely, a short exposure to turbulent flow (3 min) induced a strong increase in cell sodium content. At flow rates found in large human arteries, the onset of such ionic change required pressure levels of 50-85 mmHg. The restoration of laminar flow allowed the elimination of the excess cell sodium content, with a half-life of 3-4 h. Opening of calcium channels by the turbulent flow was suggested by the following observations: (1) nitrendipine fully prevented sodium uptake, with an inhibitory concentration of 50% of approximately 2 x 10(-7) mol/l; and (2) exposure to turbulent flow increased cytosolic free calcium content by approximately 80%. In addition to sodium uptake, turbulent flow stimulated cell uptake of exogenous cholesterol. Although the restoration of laminar flow allowed the rapid elimination of approximately two-thirds of the excess in cell cholesterol (with a half-life of 30-60 min), one-third of the excess cholesterol remained in the cells for more than 24 h. Finally, cell replication was faster in cells exposed to turbulent flow than in control cells subjected to laminar flow. The results show that turbulent flow provokes membrane ion transport changes in vascular smooth muscle cells, which are associated with enhanced cholesterol uptake and cell hyperplasia. Therefore, the departure from unidirectional laminar flow may be a pathogenic factor in primary hypertension and/or atherosclerosis.

Animals↗
PubMed1989

Ca2+ transport in muscle. A study of the Ca2+-transport ATPases in smooth muscle.

The Ca2+-transport ATPases of smooth muscle were studied. It was concluded that smooth muscle expresses at least two different Ca2+-transport ATPases. One is present in the plasma membrane with an Mr of 140-130 kDa it is stimulated by calmodulin and it could be purified by affinity chromatography on immobilized calmodulin. This ATPase could be reconstituted in artificial membrane vesicles that were then able to catalyze an ATP-dependent Ca2+-uptake. This Ca2+-transport ATPase could also be stimulated by partial proteolysis and by negatively charged phospholipids. Polyclonal and monoclonal antibodies were found to inhibit this ATPase and concomitantly the Ca2+-transport specifically in plasma membranes and not in the endoplasmic reticulum. This plasma-membrane Ca2+ pump from smooth muscle is controlled by cGMP via phosphorylation of a phosphatidylinositol kinase which phosphorylates phosphatidylinositol to phosphatidylinositol-monophosphate for which a specific binding site exists on the Ca2+-transport ATPase. The catalytic phosphoprotein intermediate of this ATPase can be easily demonstrated and this forms a highly sensitive method to detect the presence of the ATPase in different smooth muscles and even in non-muscle sources as the kidney. A second type of Ca2+ pump with an Mr of 100 kDa is found in smooth-muscle endoplasmic reticulum. By means of its catalytic phosphointermediate this pump could be characterized as similar to the cardiac/slow muscle isoform of the sarcoplasmic reticulum Ca2+ pumps, but different from the fast skeletal-muscle isoform. Immunological studies confirmed this conclusion. This endoplasmic reticulum Ca2+ pump in smooth muscle is regulated by cAMP and cGMP via phosphorylation of phospholamban. Once Ca2+ is accumulated in the lumen of the endoplasmic reticulum, it can be bound to calsequestrin. The calsequestrin of smooth muscle appears to be a similar isoform as that found in cardiac muscle. The Ca2+-transport ATPases were found to be inhibited by fluoroaluminate complexes without the involvement of GTP-binding proteins.

Biological Transport, Active↗
PubMed2006

Dynamic association between alpha-actinin and beta-integrin regulates contraction of canine tracheal smooth muscle.

The adhesion junctions of smooth muscle cells may be dynamically regulated during smooth muscle contraction, and this dynamic regulation may be important for the development of active tension. In the present study, the role of alpha-actinin during smooth muscle contraction was evaluated in tracheal smooth muscle tissues and freshly dissociated cells. Stimulation with acetylcholine (ACh) increased the localization of alpha-actinin at the membrane of freshly dissociated smooth muscle cells, and increased the amount of beta1 integrin that coprecipitated with alpha-actinin from muscle tissue homogenates. GFP-alpha-actinin fusion proteins were expressed in muscle tissues and visualized in live freshly dissociated cells. GFP-alpha-actinin translocated to the membrane within seconds of stimulation of the cells with ACh. Expression of the integrin-binding rod domain of alpha-actinin in smooth muscle tissues depressed active contraction in response to ACh. Expression of the alpha-actinin rod domain also inhibited the translocation of endogenous alpha-actinin to the membrane, and inhibited the association of endogenous alpha-actinin with beta1-integrin in alpha-actinin immunoprecipitates from tissue extracts. However, the expression of alpha-actinin rod domain peptides did not inhibit increases in myosin light chain phosphorylation or actin polymerization in response to stimulation with ACh. Results suggest that contractile stimulation of smooth muscle causes the rapid recruitment of alpha-actinin to beta-integrin complexes at the membrane, and that the recruitment of alpha-actinin to integrin complexes is necessary for active tension development in smooth muscle.

Actinin↗
PubMed1988

Comparative endocrinology-paracrinology-autocrinology of human adult large vessel endothelial and smooth muscle cells.

Endothelial and smooth muscle cells were isolated from human adult large blood vessels to compare their proliferative response to hormones and growth factors. Neural extracts and the medium from differentiated hepatoma cells were used as concentrated sources of required hormones and growth factors that supported both cell types. Active hormones and growth factors were identified from the neural extracts and hepatoma medium by substitution or direct isolation and biochemical characterization. Epidermal growth factor, lipoproteins, and heparin-binding growth factors elicited growth-stimulatory effects on both endothelial and smooth muscle cells. Both types of human vascular cells displayed 7600 to 8600 specific heparin-binding growth factor receptors per cell with a similar and apparent dissociation constant (Kd) of 200 to 250 pM. Heparin modified the response of both endothelial and smooth muscle cells to heparin-binding growth factors dependent on the type of heparin-binding growth factor and amount of heparinlike material present. In addition, heparin exerted a growth factor-independent inhibition of smooth muscle cell proliferation. Platelet-derived growth factor, insulinlike growth factors, and glucocorticoid specifically supported proliferation of smooth muscle cells with no apparent effect on endothelial cell proliferation. Growth-factorlike proteinase inhibitors had an impact specifically on endothelial cell proliferation. Transforming growth factor beta was a specific inhibitor of endothelial cells, but had a positive effect on smooth muscle cell proliferation. The results provide a framework for differential control of the two vascular cell types at normal and atherosclerotic blood vessel sites by the balance among positive and negative effectors of endocrine, paracrine and autocrine origin.

Cell Division↗
PubMed1985

Calcium- and calmodulin-dependent phosphorylase kinase activity in porcine uterine smooth muscle.

Porcine uterine smooth muscle phosphorylase kinase has been partially purified. The enzyme was activated about 1.5-2.0-fold by exogenous calmodulin. Half maximal stimulation was observed at about 100 nM calmodulin. The activation was dependent on calcium and was maximum at pH 7.5 in the range of pH from 6 to 9. This activation was completely abolished by 100 microM trifluoperazine. The result suggested that unlike slow and cardiac muscles, phosphorylase kinase of uterine smooth muscle showed similar response to calmodulin with that of fast muscle. The physiological role of the calcium and calmodulin-dependent activation of myometrium phosphorylase kinase is briefly discussed.

Animals↗
PubMed1987

Congenital smooth-muscle hamartoma.

Congenital smooth-muscle hamartomas are rare, benign tumors of the skin. Since their original description in 1969, 16 case reports have appeared in the literature, with 7 cases reported within the last year. We describe the 17th patient with this lesion and have included a review of the literature. In addition, we describe three morphologic types of smooth muscle cells-the pale cells, dark cells, and intermediate cells-found on electron microscopy, and the features that support our belief that these may reflect different stages of maturity of the smooth-muscle cells. In addition to the smooth muscle, bundles of nerve fibers (both unmyelinated and myelinated) appear to be an intrinsic part of the lesion, as are the prominent vellus hairs. Congenital smooth muscle hamartoma thus appears to be an organoid nevus.

Biopsy↗
PubMed1993

Molecular cloning of a diverged homeobox gene that is rapidly down-regulated during the G0/G1 transition in vascular smooth muscle cells.

Adult vascular smooth muscle cells dedifferentiate and reenter the cell cycle in response to growth factor stimulation. Here we describe the molecular cloning from vascular smooth muscle, the structure, and the chromosomal location of a diverged homeobox gene, Gax, whose expression is largely confined to the cardiovascular tissues of the adult. In quiescent adult rat vascular smooth muscle cells, Gax mRNA levels are down-regulated as much as 15-fold within 2 h when these cells are induced to proliferate with platelet-derived growth factor (PDGF) or serum growth factors. This reduction in Gax mRNA is transient, with levels beginning to rise between 8 and 24 h after mitogen stimulation and returning to near normal by 24 to 48 h. The Gax down-regulation is dose dependent and can be correlated with the mitogen's ability to stimulate DNA synthesis. PDGF-AA, a weak mitogen for rat vascular smooth muscle cells, did not affect Gax transcript levels, while PDGF-AB and -BB, potent mitogens for these cells, were nearly as effective as fetal bovine serum. The removal of serum from growing cells induced Gax expression fivefold within 24 h. These data suggest that Gax is likely to have a regulatory function in the G0-to-G1 transition of the cell cycle in vascular smooth muscle cells.

Animals↗
PubMed1987

Effect of an elastin growth substrate on cholesteryl ester synthesis and foam cell formation by cultured aortic smooth muscle cells.

Exposure of smooth muscle cells cultured on plastic or glass to hyperlipidemic serum did not result in the formation of foam cells. Since elastin binds serum lipids, and vascular smooth muscle cells are normally closely associated with elastin, we investigated the effects of an elastin substrate on lipid metabolism and on the accumulation of lipid vacuoles by rabbit aortic smooth muscle cells in culture. When cells were grown in plastic petri dishes, cholesteryl ester synthesis, as measured by [14C]oleate incorporation into cholesteryl esters, was 3 times greater in rabbit hyperlipidemic serum (HLS) than in normolipemic serum (NLS) (P less than 0.001). For cells of the same subculture grown on the elastin substrate, the synthetic rate was 6-fold greater in HLS compared to NLS (P less than 0.005). The cells grown on the elastin membranes in the presence of HLS contained large numbers of Oil red O stainable lipid vacuoles and resembled foam cells, while those grown in petri dishes and exposed to HLS showed only an occasional cell containing a few vacuoles. Pre-incubation in lipoprotein-deficient serum markedly enhanced the stimulatory effect of HLS on cholesteryl ester synthesis for cells growing in plastic petric dishes but had much less stimulatory effect on the cells growing on elastin membranes. These studies indicate that close association with elastin modulates the response of smooth muscle cells to hyperlipidemia and suggest a role for elastin in the formation of foam cells of smooth muscle origin during atherogenesis.

Animals↗
PubMed2000

Vascular smooth muscle and arterial calcification.

Smooth muscle cultures can calcify under certain circumstances. As a model system these cultures therefore provide information on why calcification occurs in atherosclerotic plaques. Whether all smooth muscle cells (under certain conditions), or only specific populations, can produce this mineralization has not been resolved. Demer's group has cloned calcifying vascular cells from subcultured bovine aorta and studied them in detail. They have speculated on whether the cells are smooth muscle which have altered in phenotype, or whether they are derived from a stem cell population within the artery wall. The article argues that while the normal process of smooth muscle phenotypic modulation seen in arterial repair could account for the observations, this view may be two simplistic considering the complex nature of the artery wall. Certainly there is evidence for heterogeneity of smooth muscle cells in the artery wall and recent evidence suggests that stem cells can circulate in the blood and repopulate tissues. Further studies are required to resolve the important question as to the origin of cells which produce mineralization in atheroma.

Animals↗
PubMed2026

Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome.

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

Animals↗
PubMed2006

Heaves, an asthma-like equine disease, involves airway smooth muscle remodeling.

BACKGROUND: Increased airway smooth muscle mass is a prominent feature of asthmatic airway remodeling. Airway smooth muscle hyperplasia occurs in rodent models of experimental asthma, but the relevance of such finding to spontaneously occurring disease in large mammals is unknown. OBJECTIVE: We examined horses with heaves, a naturally occurring equine asthma related to sensitization and exposure to moldy hay. We hypothesized that airway remodeling occurs in heaves and shares disease mechanisms with asthma. METHODS: We quantified the airway smooth muscle mass and the numbers of proliferating and apoptotic airway smooth muscle cells in 5 horses with heaves and 5 control horses using morphometric techniques. Cell proliferation was detected in tissue sections by immunostaining for proliferating cell nuclear antigen, and apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling of fragmented DNA. Both signals were colocalized with smooth muscle specific alpha-actin. RESULTS: Horses with heaves had a significant increase in the amount of smooth muscle in the airways (nearly triple that of the controls) associated with increased myocyte proliferation (7-fold proliferating cell nuclear antigen-positive airway myocytes) and apoptosis (6-fold). CONCLUSION: Heaves involves airway smooth muscle growth associated with myocyte hyperplasia, which may contribute to the growth, and increased myocyte apoptosis that may reflect a compensatory mechanism serving to limit the abnormal smooth muscle growth. CLINICAL IMPLICATIONS: Airway smooth muscle remodeling in heaves may be involved in the mechanism of airway hyperresponsiveness and chronic lung function impairment in a way comparable to human asthma.

Animals↗
PubMed1987

Effects of calcium on vascular smooth muscle contraction.

Calcium initiates smooth muscle contraction by binding to calmodulin and activating the enzyme myosin light chain kinase. The activated form of myosin light chain kinase phosphorylates myosin on the 20,000-dalton light chain and contractile activity ensues. Calcium may also enhance smooth muscle contractile activity by binding directly to myosin, the main component of the thick filament. Recent studies raise the possibility that the calcium-calmodulin complex may also modulate smooth muscle contractile activity by removing the inhibition imposed by caldesmon, a protein that is bound to the thin (i.e., actin-containing) filaments of smooth muscle. In vitro studies have demonstrated that the calcium-activated, phospholipid-dependent kinase, protein kinase C, can phosphorylate smooth muscle myosin at a different site than does myosin light chain kinase and down-regulate its actin-activated magnesium adenosine triphosphatase activity. This raises the possibility that protein kinase C phosphorylation of myosin may play a role in modulating vascular contractile activity in vivo.

Animals↗
PubMed2004

Acetylcholine: a novel regulator of airway smooth muscle remodelling?

Increased airway smooth muscle mass is a pathological feature that asthma and chronic obstructive pulmonary disease (COPD) have in common. This increase has gained renewed interest in view of recent developments showing that airway smooth muscle, instead of solely being a contractile partner, is capable of interacting dynamically with its environment, especially under inflammatory conditions. Airway smooth muscle cells are able to proliferate, to migrate, and to secrete chemokines, cytokines, extracellular matrix proteins and growth factors, and most importantly, to adapt to these functions by changing its phenotype from contractile to proliferative/synthetic. Conversely, switching to a (hyper)contractile phenotype may also occur. A vast number of inflammatory stimuli regulate these functions and exert their effects via excitatory G(q) or G(i)-coupled receptors. Since acetylcholine activates muscarinic M(2) and M(3) receptors in the airway smooth muscle cell membrane, which are coupled to G(i) and G(q) proteins, respectively, and since acetylcholine release may be enhanced in airway inflammation, a pathophysiological role of acetylcholine related to the above processes and exceeding contraction could be envisaged. In this review, evidence in favour of this hypothesis, based on recent data that show a role for muscarinic receptors in modulating airway smooth muscle proliferation, contractility and contractile protein expression is discussed. Based on these findings, we postulate that endogenous acetylcholine contributes to airway remodeling in asthma and COPD.

Acetylcholine↗
PubMed1997

Small heat shock proteins and vasospasm in human umbilical artery smooth muscle.

Human umbilical artery smooth muscle is uniquely refractory to cyclic nucleotide-dependent vasorelaxation. Small heat shock proteins (HSPs) have been implicated as contractile regulatory proteins. Thus, we hypothesized that alterations in the phosphorylation of small HSPs may contribute to human umbilical artery smooth muscle vasospasm. Physiologic contractile responses were determined in a muscle bath and compared with phosphorylation events determined with whole-cell phosphorylation and 2-dimensional gel electrophoresis. Precontraction of bovine carotid artery smooth muscle with serotonin followed by relaxation with forskolin was associated with increases in the phosphorylation of HSP27 and HSP20. Precontraction of umbilical artery with serotonin followed by forskolin treatment led to increases in the phosphorylation of HSP27. However, the umbilical artery smooth muscle did not relax, nor was there an increase in the phosphorylation of HSP20 with forskolin treatment. These data suggest that impaired cyclic nucleotide-dependent relaxation of umbilical artery smooth muscle is associated with a lack of phosphorylation of HSP20.

Colforsin↗
PubMed2002

The physiology, pathophysiology and therapeutic potential of gap junctions in smooth muscle.

Phenotypic variability in smooth muscle cells accounts, in large part, for the incredible functional diversity required of the involuntary hollow organs of the body (i.e., respiratory passages, blood vessels, gastrointestinal tract, urogenital tract, etc.). In all instances coordination of smooth muscle cell responses, that is, contraction and relaxation, is critical to normal organ function. While numerous biological mechanisms exist for coordinating smooth muscle cell responses, intercellular communication through gap junctions represents a common denominator present in all organ systems. In this report, we review the evidence documenting the presence and functional significance of myocyte gap junctions to physiologically distinct organ systems, and furthermore, provide some examples of their putative roles in organ pathology. Finally, we advance the thesis that despite their ubiquity and heterogeneous expression, gap junctions are nonetheless potentially attractive therapeutic targets for the treatment of certain smooth muscle disorders. Their therapeutic efficacy will necessarily hinge on the existence of connexin isoform-selective junctional effects. The overall rationale for targeting the intercellular pathway is therefore analogous to strategies that target other ubiquitously expressed ion channels, such as calcium or potassium channels. Such strategies have proved efficacious for the treatment of a wide range of human smooth muscle disorders including hypertension, urinary incontinence and sexual function.

Animals↗
PubMedDate not supplied

Calcium signalling in smooth muscle.

Calcium signalling in smooth muscles is complex, but our understanding of it has increased markedly in recent years. Thus, progress has been made in relating global Ca2+ signals to changes in force in smooth muscles and understanding the biochemical and molecular mechanisms involved in Ca2+ sensitization, i.e. altering the relation between Ca2+ and force. Attention is now focussed more on the role of the internal Ca2+ store, the sarcoplasmic reticulum (SR), global Ca2+ signals and control of excitability. Modern imaging techniques have shown the elaborate SR network in smooth muscles, along with the expression of IP3 and ryanodine receptors. The role and cross-talk between these two Ca(2+) release mechanisms, as well as possible compartmentalization of the SR Ca2+ store are discussed. The close proximity between SR and surface membrane has long been known but the details of this special region to Ca2+ signalling and the role of local sub-membrane Ca2+ concentrations and membrane microdomains are only now emerging. The activation of K+ and Cl- channels by local Ca2+ signals, can have profound effects on excitability and hence contraction. We examine the evidence for both Ca2+ sparks and puffs in controlling ion channel activity, as well as a fundamental role for Ca2+ sparks in governing the period of inexcitability in smooth muscle, i.e. the refractory period. Finally, the relation between different Ca2+ signals, e.g. sparks, waves and transients, to smooth muscle activity in health and disease is becoming clearer and will be discussed.

Animals↗