Intercellular communication in smooth muscle

The functioning of a group of cells as a tissue depends on intercellular communication; an example is the spread of action potentials through intestinal tissue resulting in synchronized contraction. Recent evidence for cell heterogeneity within smooth muscle tissues has renewed research into cell coupling.Electrical coupling is essential for propagation of action potentials in gastrointestinal smooth muscle.Metabolic coupling may be involved in generation of pacemaker activity. This review deals with the role of cell coupling in tissue function and some of the issues discussed are the relationship between electrical synchronization and gap junctions, metabolic coupling, and the role of interstitial cells of Cajal in coupling.     

Adiponectin as a tissue regenerating hormone: more than a metabolic function

The great interest that scientists have for adiponectin is primarily due to its central metabolic role. Indeed, the major function of this adipokine is the control of glucose homeostasis that it exerts regulating liver and muscle metabolism. Adiponectin has insulin-sensitizing action and leads to down-regulation of hepatic gluconeogenesis and an increase of fatty acid oxidation. In addition, adiponectin is reported to play an important role in the inhibition of inflammation. The hormone is secreted in full-length form, which can either assemble into complexes or be converted into globular form by proteolytic cleavage. Over the past few years, emerging publications reveal a more varied and pleiotropic action of this hormone. Many studies emphasize a key role of adiponectin during tissue regeneration and show that adiponectin deficiency greatly inhibits the mechanisms underlying tissue renewal. This review deals with the role of adiponectin in tissue regeneration, mainly referring to skeletal muscle regeneration, a process in which adiponectin is deeply involved. In this tissue, globular adiponectin increases proliferation, migration and myogenic properties of both resident stem cells (namely satellite cells) and non-resident muscle precursors (namely mesoangioblasts). Furthermore, skeletal muscle could be a site for the local production of the globular form that occurs in an inflamed environment. Overall, these recent findings contribute to highlight an intriguing function of adiponectin in addition to its well-recognized metabolic action.     

Response of vascular mesenchymal stem/progenitor cells to hyperlipidemia

Hyperlipidemia is a risk factor for atherosclerosis that is characterized by lipid accumulation, inflammatory cell infiltration, and smooth muscle cell proliferation. It is well known that hyperlipidemia is a stimulator for endothelial dysfunction and smooth muscle cell migration during vascular disease development. Recently, it was found that vessel wall contains a variable number of mesenchymal stem cells (MSCs) that are quiescent in physiological conditions, but can be activated by a variety of stimuli, e.g., increased lipid level or hyperlipidemia. Vascular MSCs displayed characteristics of stem cells which can differentiate into several types of cells, e.g., smooth muscle cells, adipocytic, chondrocytic, and osteocytic lineages. In vitro, lipid loading can induce MSC migration and chemokines secretion. After MSC migration into the intima, they play an essential role in inflammatory response and cell accumulation during the initiation and progression of atherosclerosis. In addition, MSC transplantation has been explored as a therapeutic approach to treat atherosclerosis in animal models. In this review, we aim to summarize current progress in characterizing the identity of vascular MSCs and to discuss the mechanisms involved in the response of vascular stem/progenitor cells to lipid loading, as well as to explore therapeutic strategies for vascular diseases and shed new light on regenerative medicine.     

Sphingosine 1-phosphate induces differentiation of adipose tissue-derived mesenchymal stem cells towards smooth muscle cells

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid which regulates multiple biological parameters in a number of cell types, including stem cells. Here we report, for the first time, that S1P dose-dependently stimulates differentiation of adipose tissue-derived mesenchymal stem cells (ASMC) towards smooth muscle cells. Indeed, S1P not only induced the expression of smooth muscle cell-specific proteins such as α-smooth muscle actin (αSMA) and transgelin, but also profoundly affected ASMC morphology by enhancing cytoskeletal F-actin assembly, which incorporated αSMA. More importantly, S1P challenge was responsible for the functional appearance of Ca²⁺ currents, characteristic of differentiated excitable cells such as smooth muscle cells. By employing various agonists and antagonists to inhibit S1P receptor subtypes, S1P₂ turned out to be critical for the pro-differentiating effect of S1P, while S1P₃ appeared to play a secondary role. This study individuates an important role of S1P in AMSC which can be exploited to favour vascular regeneration. Received 06 March 2009; accepted 17 March 2009     

Retinoic acid enhances the proliferation of smooth muscle cells

Retinoic acid (RA, 10(-5) - 10(-7) M) is shown to enhance the proliferation of cultured rat aortic smooth muscle cells (SMC). This effect is not connected with a synergistic action of RA together with serum mitogens. Moreover, the expression of L1, a surface antigen specific for modulated SMC entering the cell cycle, is amplified by RA treatment.     

The signal transducing system coupled to serotonin-S2 receptors

The signal transducing system coupled to the serotonin-S2 receptor on platelets involves metabolism of inositol-containing phospholipid, elevation of intracellular free Ca2+ and activation of protein kinase C. Evidence for coupling of the serotonin-S2 receptor to the same signal transducing system in brain and smooth muscle tissue is reviewed.     

Intercellular dye-coupling in intestinal smooth muscle. Are gap junctions required for intercellular coupling?

Summary The dye Lucifer Yellow was injected into single smooth muscle cells in the guinea pig small intestine in order to study intercellular coupling. Dye-coupling was observed in both the circular and longitudinal muscle layers and was markedly reduced when the intercellular pH was lowered. These results suggest the presence of gap junctions among intestinal muscle cells, but are inconsistent with previous ultrastructural studies that failed to demonstrate such junctions in the longitudinal muscle.     

Intercellular dye-coupling in intestinal smooth muscle. Are gap junctions required for intercellular coupling?

The dye Lucifer Yellow was injected into single smooth muscle cells in the guinea pig small intestine in order to study intercellular coupling. Dye-coupling was observed in both the circular and longitudinal muscle layers and was markedly reduced when the intercellular pH was lowered. These results suggest the presence of gap junctions among intestinal muscle cells, but are inconsistent with previous ultrastructural studies that failed to demonstrate such junctions in the longitudinal muscle.     

A method for the detection of chemotaxis in mammalian tissue cells

Summary A new method is described of culture of mammalian tissue cells beneath a solid medium, permitting the assessment of growth-promoting, growth-inhibiting and chemotactic substances.Our thanks are due to Mr.D. S. Leake, who provided the smooth muscle cell suspensions; and to Mr.J. F. Stevenson, for expertise in preparing the medium. This work is supported by the British Heart Foundation, Grant No. 528.     

Retinoic acid enhances the proliferation of smooth muscle cells

Summary Retinoic acid (RA, 10^–5–10^–7 M) is shown to enhance the proliferation of cultured rat aortic smooth muscle cells (SMC). This effect is not connected with a synergistic action of RA together with serum mitogens. Moreover, the expression of L1, a surface antigen specific for modulated SMC entering the cell cycle, is amplified by RA treatment.     

Development and pathologies of the arterial wall

Arteries consist of an inner single layer of endothelial cells surrounded by layers of smooth muscle and an outer adventitia. The majority of vascular developmental studies focus on the construction of endothelial networks through the process of angiogenesis. Although many devastating vascular diseases involve abnormalities in components of the smooth muscle and adventitia (i.e., the vascular wall), the morphogenesis of these layers has received relatively less attention. Here, we briefly review key elements underlying endothelial layer formation and then focus on vascular wall development, specifically on smooth muscle cell origins and differentiation, patterning of the vascular wall, and the role of extracellular matrix and adventitial progenitor cells. Finally, we discuss select human diseases characterized by marked vascular wall abnormalities. We propose that continuing to apply approaches from developmental biology to the study of vascular disease will stimulate important advancements in elucidating disease mechanism and devising novel therapeutic strategies.     

Calcium and sodium distribution and movements in smooth muscle

Electron probe microanalysis (EPMA) has been used to study the subcellular distribution of Ca, Na, K, Cl, and Mg in smooth muscle. The EPMA results indicate that the sarcoplasmic reticulum (SR) is the major intracellular source and sink of activator Ca: norepinephrine decreases the Ca content of the junctional SR in portal vein smooth muscle. Mitochondria do not play a significant role in regulating cytoplasmic free Ca2+, but mitochondrial Ca content can be altered to a degree compatible with suggestions that fluctuations in matrix Ca contribute to the control of mitochondrial metabolism. The rise in total cytoplasmic Ca during a maintained, maximal contraction is very much greater than the rise in free Ca2+, and is probably in excess of the known binding sites available on calmodulin and myosin. Cell Ca is not increased in normal cells that are Na-loaded. The non-Donnan distribution of Cl is not due to compartmentalization, but reflects high cytoplasmic Cl. Na-loading of smooth muscle in K-free solutions is temperature dependent, and may exhibit cellular heterogeneity undetected by conventional techniques. The total cell Mg is equivalent to approximately 12 mM, and less than 50% of it can be accounted for by binding to ATP and to actin. Mitochondrial monovalent cations in smooth muscle are relatively rapidly exchangeable.     

Calcium and sodium distribution and movements in smooth muscle

Summary Electron probe microanalysis (EPMA) has been used to study the subcellular distribution of Ca, Na, K. Cl, and Mg in smooth muscle. The EPMA results indicate that the sarcoplasmic reticulum (SR) is the majorintracellular source and sink of activator Ca: norepinephrine decreases the Ca content of the junctional SR in portal vein smooth muscle. Mitochondria do not play a significant role in regulating cytoplasmic free Ca²⁺, but mitochondrial Ca content can be altered to a degree compatible with suggestions that fluctuations in matrix Ca contribute to the control of mitochondrial metabolism. The rise intotal cytoplasmic Ca during a maintained, maximal contraction is very much greater than the rise in free Ca²⁺, and is probably in excess of the known binding sites available on calmodulin and myosin. Cell Ca is not increased in normal cells that are Na-loaded. The non-Donnan distribution of Cl is not due to compartmentalization, but reflects high cytoplasmic Cl. Na-loading of smooth muscle in K-free solutions is temperature dependent, and may exhibit cellular heterogeneity undetected by conventional techniques. The total cell Mg is equivalent to approximately 12 mM, and less than 50% of it can be accounted for by binding to ATP and to actin. Mitochondrial monovalent cations in smooth muscle are relatively rapidly exchangeable.     

Pleiotropic effects of sonic hedgehog on muscle satellite cells

Muscle satellite cells are believed to form a stable, self-renewing pool of stem cells in adult muscle where they function in tissue growth and repair. A regulatory disruption of growth and differentiation of these cells is assumed to result in tumor formation. Here we provide for the first time evidence that sonic hedgehog (Shh) regulates the cell fate of adult muscle satellite cells in mammals. Shh promotes cell division of satellite cells (and of the related model C2C12 cells) and prevents their differentiation into multinucleated myotubes. In addition, Shh inhibits caspase-3 activation and apoptosis induced by serum deprivation. These effects of Shh are reversed by simultaneous administration of cyclopamine, a specific inhibitor of the Shh pathway. Taken together, Shh acts as a proliferation and survival factor of satellite cells in the adult muscle. Our results support the hypothesis of the rhabdomyosarcoma origin from satellite cells and suggest a role for Shh in this process.Received 23 February 2005; received after revision 2 May 2005; accepted 9 June 2005     

Lipid mediators in epithelial cell-cell interactions

Epithelial cells which line mucosal surfaces (e.g. lung, intestine) play a central role in the coordination of the inflammatory response. In both the healthy and diseased mucosa, epithelia lie anatomically positioned in close proximity to a number of other cell types, including leukocytes, fibroblasts, smooth muscle cells and vascular endothelia. This complex architecture supports a unique microenvironment for biochemical cell-cell crosstalk. Our previous studies and work by others have elucidated lipid mediator signaling networks emanating from epithelial cell-cell interactive pathways, and have defined a number of targets for development of effective therapeutics. This short review will focus on recently defined pathways of lipid mediator function in the mucosa, particularly with regard to the role of the epithelium.     

The possible role of glutamine in some cells of the immune system and the possible consequence for the whole animal

Glutamine is important for the function of lymphocytes and macrophages. A role for the high rate of glutamine utilisation by these cells is presented. Since muscle syntheses, stores and releases glutamine, this tissue may play a role in the immune response. Since the number of immune cells utilising glutamine may be large, the demand for glutamine from muscle, especially during trauma sepsis or burns, may be very high. A speculative suggestion is put forward that this requirement for glutamine from muscle may play a role in cachexia under some of these conditions.     

Cell–cell junctional mechanotransduction in endothelial remodeling

The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell–cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell–cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell–cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell–cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.     

Ciliated fibroblasts and smooth muscle cells in the rat uterus

Ciliation in endometrial fibroblasts and myometrial muscle cells of the rat was examined by transmission electron microscopy. Quantification of the number of ciliated cells during the estrus cycle did not show any firm relationship between ciliation and ovarian hormonal activity. In the case of most cilia, there is a spatial relationship between their basal centrioles and the Golgi complex, so that a Golgi-cilium complex is created. A possible role of ciliation in uterine fibroblasts and smooth muscle cells is discussed.