Journal of Smooth Muscle Research最新文献

Pulmonary arterial hypertension (PAH) is an intractable vascular disease characterized by a progressive increase in pulmonary vascular resistance caused by pulmonary vascular remodeling, which ultimately leads to right-sided heart failure. PAH remains incurable, despite the development of PAH-targeted therapeutics centered on pulmonary artery relaxants. It is necessary to identify the target molecules that contribute to pulmonary artery remodeling. Transient receptor potential (TRP) channels have been suggested to modulate pulmonary artery remodeling. Our study focused on the transient receptor potential ion channel subfamily M, member 7, or the TRPM7 channel, which modulates endothelial-to-mesenchymal transition and smooth muscle proliferation in the pulmonary artery. In this review, we summarize the role and expression profile of TRPM7 channels in PAH progression and discuss TRPM7 channels as possible therapeutic targets. In addition, we discuss the therapeutic effect of a Chinese herbal medicine, Ophiocordyceps sinensis (OCS), on PAH progression, which partly involves TRPM7 inhibition.

Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are major cell types that control vascular function, and hence dysfunction of these cells plays a key role in the development and progression of vasculopathies. Abnormal vascular responsiveness to vasoactive substances including vasoconstrictors and vasodilators has been observed in various arteries in diseases including diabetes, hypertension, chronic kidney diseases, and atherosclerosis. Several substances derived from ECs tightly control vascular function, such as endothelium-derived relaxing and contracting factors, and it is known that abnormal vascular signaling of these endothelium-derived substances is often observed in various diseases. Derangement of signaling in VSMCs and altered function influence vascular reactivity to vasoactive substances and tone, which are important determinants of vascular resistance and blood pressure. However, understanding the molecular mechanisms underlying abnormalities of vascular functions in pathological states is difficult because multiple substances interact in the development of these processes. Advanced glycation end products (AGEs), a heterogeneous group of bioactive compounds, are thought to contribute to vascular dysfunction, which in turn cause the development of several diseases including diabetes, hypertension, stroke, and atherosclerosis. A growing body of evidence suggests that AGEs could affect these cells and modulate vascular function. This study is focused on the link between AGEs and functions of ECs and VSMCs, particularly the modulative effects of AGEs on vascular reactivities to vasoactive substances.

The characteristic mechanical activities of the smooth muscles found in all organs of the body are highly variable and depend mainly on the spatial arrangement of the muscle cells and the stroma: mass, orientation, relationships, links, constraints, which are deployed in various configurations. These structural features are examined here for their mechanical relevance, in light and electron microscopic views of several muscles of viscera and blood vessels, in a selection of mammalian species. Smooth muscles are incompressible and therefore maintain constant volume. They do not have available space and any movement of a part requires displacement of another part. Most of them have no terminations or points of attachment, and in hollow organs such as intestines, blood vessels and uro-genital tract they usually form structures closed onto themselves, such as rings or bag-like containers In these situations, changes in the size of the lumen is achieved very efficiently by a concentric inward enlargement that accompanies muscle contraction. The longitudinal arrangement of collagen blocks an elongation of small blood vessels upon contraction, further enhancing the efficiency of lumen reduction. In other muscles, links between layers and special arrangements of the stroma allow both shortening and elongation of a tubular organ to occur. The mechanics of smooth muscles has many characteristic features (some unique, some shared with those of hydrostats, some at variance with other muscles) and histological data are a contribution to our understanding of these properties.

Background: Serotonin (5-hydroxytryptamine; 5-HT) performs a variety of functions in the body including the modulation of muscle tone in respiratory airways. Several studies indicate a possible role of 5-HT in the pathophysiology of bronchial hyperresponsiveness. However, the receptors and the molecular mechanisms by which 5-HT acts on airway smooth muscle (ASM) continue to be controversial. Most of the evidence suggests the participation of different subtypes of receptors in an indirect response. This study supports the proposal that 5-HT directly contracts ASM and characterizes pharmacologically the subtypes of serotonergic receptors involved. The characterization was carried out by using selective antagonists in an organ bath model allowing study of the smooth muscle of segments of bovine trachea.

Results: The results obtained show that 5-HT_2A receptors are the main mediators of the direct contractile response of bovine ASM, with the cooperation of the 5-HT₇, 5-HT₃ and 5-HT_1B/D receptors. Also, it was observed that the muscle response to serotonin is developed more slowly and to a lesser extent in comparison with the response to cholinergic stimulation.

Conclusion: Overall, the receptors that mediate the direct serotonergic contraction of the smooth muscle of the bovine trachea are 5-HT_2A, 5-HT₇, 5-HT₃ and 5-HT_1B/D receptors.

Intestinal spasms are violent contractions that occur in the intestine, which cause discomfort to people who have them. Medicinal plants are widely used in traditional Moroccan medicine to treat these problems, among these being Artemisia campestris L. This study aims to evaluate the relaxant and antispasmodic effects of an aqueous extract of this plant (ACAE). It was performed in vitro on isolated segments of both isolated rat and rabbit jejunum mounted in an organ bath and tension recordings made via an isotonic transducer. ACAE caused a myorelaxant effect on baseline rabbit jejunum contractions in a dose-dependent and reversible manner with an IC₅₀ of 1.52 ± 0.12 mg/ml. This extract would not act via adrenergic receptors pathway. On the other hand, the extract caused a dose-dependent relaxation of the jejunum tone in rat jejenum segments pre-contracted with either Carbachol (CCh; 10^-6 M) or high K⁺ (KCl 75 mM) with an IC₅₀ = 0.49 ± 0.02 mg/ml and 0.36 ± 0.02 mg/ml respectively. In the presence of different doses of the extract, the maximum response to CCh and CaCl₂ was significantly reduced. This demonstrates that ACAE acts on both muscarinic receptors and voltage-dependent calcium channels. Thus, the plant extract acted on both muscarinic and nicotinic receptors and acts on the guanylate cyclase pathway, but not the nitric oxide pathway. These results indicate the mechanism by which Artemisia campestris L. acts as an effective antispasmodic agent in traditional Moroccan medicine.

Pompe disease is a lysosomal storage disease caused by mutations within the GAA gene, which encodes acid α-glucosidase (GAA)-an enzyme necessary for lysosomal glycogen degradation. A lack of GAA results in an accumulation of glycogen in cardiac and skeletal muscle, as well as in motor neurons. The only FDA approved treatment for Pompe disease-an enzyme replacement therapy (ERT)-increases survival of patients, but has unmasked previously unrecognized clinical manifestations of Pompe disease. These clinical signs and symptoms include tracheo-bronchomalacia, vascular aneurysms, and gastro-intestinal discomfort. Together, these previously unrecognized pathologies indicate that GAA-deficiency impacts smooth muscle in addition to skeletal and cardiac muscle. Thus, we sought to characterize smooth muscle pathology in the airway, vascular, gastrointestinal, and genitourinary in the Gaa^-/- mouse model. Increased levels of glycogen were present in smooth muscle cells of the aorta, trachea, esophagus, stomach, and bladder of Gaa^-/- mice, compared to wild type mice. In addition, there was an increased abundance of both lysosome membrane protein (LAMP1) and autophagosome membrane protein (LC3) indicating vacuolar accumulation in several tissues. Taken together, we show that GAA deficiency results in subsequent pathology in smooth muscle cells, which may lead to life-threatening complications if not properly treated.

This review highlights molecular mechanisms of anti-inflammatory and protective effects of the nuclear transcription factor, peroxisome proliferator-activated receptor γ (PPARγ) in vascular tissue. PPARγ is an ubiquitously expressed nuclear factor, and well-studied in adipose tissue and inflammatory cells. Additionally, beneficial effects of vascular PPARγ's on atherosclerosis and vascular remodeling/dysfunction have been reported although the detailed mechanism remains to be completely elucidated. Clinical and basic studies have shown that the synthetic PPARγ ligands, thiazolidinediones (TZDs), have protective effects against cardiovascular diseases such as atherosclerosis. Recent studies utilizing genetic tools suggested that those protective effects of TZDs on cardiovascular diseases are not due to a consequence of improvement of insulin resistance, but may be due to a direct effect on PPARγ's in vascular endothelial and smooth muscle cells. In this review, we discuss proposed mechanisms by which the vascular PPARγ regulates vascular inflammation and remodeling/dysfunction especially in smooth muscle cells.

Vascular conductance (VC) regulation involves a continuous balance between metabolic vasodilation and sympathetic vasoconstriction. Endurance exercise challenges the sympathetic control on VC due to attenuated sympathetic receptor responsiveness and persistence of muscle vasodilation, especially in endurance athletes, predisposing them to blood pressure control dysfunctions. This study assessed whether acute handgrip-mediated sympathetic activation (SYMP) restrains sudden leg vasodilation before and after a half-marathon. Prior to, and within the 20 min following the race, 11 well-trained runners underwent two single passive leg movement (SPLM) tests to suddenly induce leg vasodilation, one without and the other during SYMP. Leg blood flow and mean arterial pressure were measured to assess changes in leg VC. Undertaking 60 sec of SYMP reduced the baseline leg VC both before (4.0 ± 1.0 vs. 3.3 ± 0.7 ml/min/mmHg; P=0.01; NO SYMP vs. SYMP, respectively) and after the race (4.6 ± 0.8 vs. 3.9 ± 0.8 ml/min/mmHg; P=0.01). However, SYMP did not reduce leg peak vasodilation immediately after the SPLM either before (11.5 ± 4.0 vs. 12.2 ± 3.8 ml/min/mmHg; P=0.35) or after the race (7.2 ± 2.0 vs. 7.3 ± 2.6 ml/min/mmHg; P=0.96). Furthermore, SYMP did not blunt the mean leg vasodilation over the 60 sec after the SPLM before (5.1 ± 1.7 vs. 5.9 ± 2.5 ml/min/mmHg; P=0.14) or after the race (4.8 ± 1.3 vs. 4.2 ± 1.5 ml/min/mmHg; P=0.26). This data suggest that the release of local vasoactive agents effectively opposes any preceding handgrip-mediated augmented vasoconstriction in endurance athletes before and after a half-marathon. Handgrip-mediated SYMP might improve normal vasoconstriction while athletes are still, but not necessarily while they move, as movements can induce a release of vasoactive molecules.

There are various refractory chronic inflammatory diseases related to the genitourinary tract, such as interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. It has been reported that in the general population, these diseases are related to other chronic illnesses, such as irritable bowel syndrome or vulvodynia. Herein, we review papers regarding pelvic organ cross-sensitization, a factor which is considered to contribute to these relationships. Several other researchers and ourselves have reported that noxious stimuli from a diseased pelvic organ are transmitted to an adjacent normal structure via shared sensory neural pathways at the prespinal, spinal, and supraspinal levels, resulting in functional changes in the adjacent normal structure. In conclusion, since there are few treatments to cure interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome completely, further studies regarding organ cross-sensitization may provide new insights into the pathophysiology and treatment strategies for these diseases.

Exposure to unpleasant tastes leads to disturbances of interdigestive gastric myoelectrical activity (GMA) and may affect sympathetic/parasympathetic balance (SPB). We made a careful study to determine whether taste stimulation modulates the postprandial GMA, SPB, and gastric emptying (GE) of a solid meal. Eighteen healthy volunteers (9F/9M) entered the study. On six separate days, we recorded a four-channel electrogastrogram from each volunteer during a 35-min fasting period, then for 90 min after ingestion of a solid test meal of 300 kcal. GE was measured using a ¹³C-octanoic acid breath test. Heart rate variability (HRV) analysis was simultaneously performed. At the start of the 21st min after the test meal, subjects received an agar cube delivering either a sweet, salty, sour, or bitter taste, which they kept in the mouth for 35 min. Control procedures involved sessions performed with a tasteless agar cube, and without any stimulation. There was no effect of the experimental intervention upon the relative power share of particular GMA rhythms. Stimulation with the salty and the bitter taste evoked a statistically significant increase in the dominant frequency, whereas the sweet and sour taste did not affect it. Taste stimulation did not interfere with the meal-induced rise in the dominant power, nor affect slow wave coupling. The kinetics of the solid GE remained unchanged by the intervention. None of the taste stimulations affected the postprandial SPB. Taste stimulation elicited after ingestion of a meal, in contrast to that during a fast, did not adversely modify the postprandial pattern of either the GMA or SPB, nor affect the GE of solids.