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At least 469 records · Page 26Linked to original sources
PubMed1995

Integrin-mediated collagen matrix reorganization by cultured human vascular smooth muscle cells.

Vascular smooth muscle cells perform the important function of modulation of vascular extracellular matrix. Because integrins mediate many cell-matrix interactions, the role of integrins in reorganization of collagen by cultured human vascular smooth muscle cells was studied. Immunoprecipitation demonstrated that human vascular smooth muscle cells express multiple beta 1 integrins. Monoclonal antibody A2-IIE10 (a blocking anti-alpha 2 antibody) inhibited adhesion of smooth muscle cells to collagen by 31%. The blocking anti-alpha 1 antibody 1B3.1 inhibited adhesion by 40%, whereas a blocking anti-alpha 3 antibody had no effect on adhesion. When 1B3.1 and A2-IIE10 were both used, a 79% reduction in adhesion was observed, indicating that active alpha 1 and alpha 2 integrins cooperatively mediate adhesion. The blocking anti-beta 1 antibody Mab13 abolished smooth muscle cell-mediated gel contraction, and the alpha 2-blocking antibody A2-IIE10 had a dose-dependent partial inhibitory effect (37%). In contrast, blocking antibodies to alpha 1 and alpha 3 had no effect. When anti-alpha 1 (1B3.1) and anti-alpha 2 (A2-IIE10) monoclonal antibodies were combined, no synergistic effect on inhibition of gel contraction was observed. Surprisingly, collagen gel contraction was inhibited by 46% by an anti-beta 1 antibody (TS2/16) known for its stimulatory effect on cell adhesion. Thus, whereas alpha 1 beta 1 and alpha 2 beta 1 integrins both participate in adhesion of vascular smooth muscle cells to collagen, only alpha 2 beta 1 integrins mediate collagen reorganization. In addition, collagen reorganization appears to be a dynamic process, adversely affected by excessive adhesion strengthening.

Cell Adhesion↗
PubMed1995

Pathologic considerations of uterine smooth muscle tumors.

Smooth muscle tumors are the most common type of uterine neoplasm. The vast majority of such tumors are benign leiomyomas. Leiomyosarcomas fortunately are relatively infrequent. A variety of gross and microscopic features may be found in both benign and malignant tumors and great care must be taken not to mistake leiomyomas with atypical or unusual features of leiomyosarcomas. Individual features, such as hypercellularity, necrosis, nuclear atypia, mitotic figures, and intravascular growth, are ominous but must be interpreted with caution because variants of benign leiomyoma may contain such changes.

Adult↗
PubMed2006

MEK hyperphosphorylation coincides with cell cycle shut down of cultured smooth muscle cells.

Smooth muscle cells (SMCs) form the backbone of arteries and their proliferation hallmarks collateral vessel growth, a process termed arteriogenesis, as well as pathogenic responses such as restenosis. Since signaling pathways in SMCs are the main targets for therapeutic interventions, we aimed to determine how and to what extent the activation of the ubiquitous MEK-ERK signaling pathway correlates with important in vivo phenomena such as dedifferentiation, nuclear activation and proliferation of SMCs. Specificity of this pathway was monitored using MEK inhibitors UO126 and PD98059 in platelet derived growth factor-AB (PDGF-AB)- and fibroblast growth factor-2 (FGF-2)-stimulated SMCs. PDGF-AB induced a rapid MEK activation followed by phosphorylation of the MEK substrates ERK1/2 while FGF-2 showed a less pronounced and delayed activation. Both growth factors triggered a marked phosphorylation of c-Myc and expression of Egr1. Pretreatment with MEK inhibitors suppressed the activation of the ERK cascade, abolished the down-regulation of desmin and led to cell cycle arrest. However, the reversibility of p27Kip1 down-regulation by UO126 was mainly observed after PDGF-AB stimulation, indicating MEK independent p27Kip1 down-regulation by FGF-2. Surprisingly, treatment of SMCs with UO126 or PD98059 increased the level of MEK phosphorylation in a dose dependent manner at serine residues 217/221 in the presence as well as in the absence of both growth factors. Our results strongly imply that depending on the environmental context phosphorylation of serines 217/221 serves as an "on" as well as an "off " switch.

Animals↗
PubMed2000

Mitogen-activated signaling and cell cycle regulation in airway smooth muscle.

Increased airway smooth muscle mass has been demonstrated in patients with bronchopulmonary dysplasia and asthma. These data highlight the need for a precise understanding of the events involved in airway smooth muscle mitogenesis. To that end, investigators have developed cell culture systems adopting tracheal and bronchial myocytes from different species. A growing body of literature suggests that common signal transduction pathways regulate airway smooth muscle cell cycle entry across species lines. This review summarizes what is known about mitogen-activated signal transduction in airway smooth muscle cells. The extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI 3-kinase) pathways appear to be major positive regulators of airway smooth muscle proliferation. It is also conceivable that growth factor stimulation of airway smooth muscle simultaneously elicits signaling through negative regulatory pathways such as the p38 mitogen-activated protein (MAP) kinase pathway, perhaps as a safeguard against excessive growth.

Animals↗
PubMed2006

H(2)O(2)-induced kinetic and chemical modifications of smooth muscle myosin: correlation to effects of H(2)O(2) on airway smooth muscle.

The effect of H(2)O(2) on smooth muscle heavy meromyosin (HMM) and subfragment 1 (S1) was examined. The number of molecules that retained the ability to bind ATP and the actinactivated rate of P(i) release were measured by single-turnover kinetics. H(2)O(2) treatment caused a decrease in HMM regulation from 800- to 27-fold. For unphosphorylated and phosphorylated heavy meromyosin and for S1, approximately 50% of the molecules lost the ability to bind to ATP. H(2)O(2) treatment in the presence of EDTA protected against ATPase inactivation and against the loss of total ATP binding. Inactivation of S1 versus time correlated to a loss of reactive thiols. Treatment of H(2)O(2)-inactivated phosphorylated HMM or S1 with dithiothreitol partially reactivated the ATPase but had no effect on total ATP binding. H(2)O(2)-inactivated S1 contained a prominent cross-link between the N-terminal 65-kDa and C-terminal 26-kDa heavy chain regions. Mass spectral studies revealed that at least seven thiols in the heavy chain and the essential light chain were oxidized to cysteic acid. In thiophosphorylated porcine tracheal muscle strips at pCa 9 + 2.1 mM ATP, H(2)O(2) caused a approximately 50% decrease in the amplitude but did not alter the rate of force generation, suggesting that H(2)O(2) directly affects the force generating complex. Dithiothreitol treatment reversed the H(2)O(2) inhibition of the maximal force by approximately 50%. These data, when compared with the in vitro kinetic data, are consistent with a H(2)O(2)-induced loss of functional myosin heads in the muscle.

Actins↗
PubMed1997

Stimulation of imidazoline receptors inhibits proliferation of human coronary artery vascular smooth muscle cells.

Vascular smooth muscle cells of rat aorta express imidazoline receptors whose stimulation, by drugs or an endogenous ligand, agmatine, inhibits serum-stimulated proliferation. We investigated whether imidazoline receptors are expressed in human vascular smooth muscle cells if their stimulation is antiproliferative. Cultured human coronary artery vascular smooth muscle cells express a nonadrenergic binding site for 3H-idazoxan and an imidazoline receptor-binding protein as revealed by immunocytochemical and immunoblot analyses with a specific antibody. Idazoxan and agmatine dose-dependently inhibited serum-stimulated proliferation of these cells as measured by the incorporation of 3H-thymidine (IC50: 5 and 70 micromol/L, respectively) and serum-stimulated expression of proliferating cell nuclear antigen and cell numbers. The agents inhibited proliferation of human and rat (aorta) smooth muscle cells stimulated by either norepinephrine (6560+/-440 disintegrations per minute norepinephrine versus 3345+/-220 norepinephrine and idazoxan), angiotensin II (7680+/-335 disintegrations per minute angiotensin II versus 3769+/-450 angiotensin II and idazoxan), or platelet-derived growth factor (IC50: 3 micromol/L for idazoxan and 40 micromol/L for agmatine), indicating inhibition of mitosis mediated by G-protein or receptor tyrosine kinase pathways. We conclude that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways. Agmatine, synthesized in endothelium, may act as a paracrine regulator of vascular smooth muscle cell proliferation through imidazoline receptors, and agents acting at this site may be useful in treating vascular hyperplasia.

Adrenergic alpha-Antagonists↗
PubMed1998

Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in arterial smooth muscle cells.

PURPOSE: Smooth muscle cell proliferation is a key event in the development of intimal hyperplasia after arterial injury. Heparin can suppress smooth muscle cell proliferation in vitro and prevents intimal hyperplasia after arterial injury, but the mechanisms of action are poorly understood. Recently, we observed that heparin inhibited serum-induced activation of mitogen-activated protein kinase in smooth muscle cells, but heparin did not inhibit signaling induced by platelet-derived growth factor BB and basic fibroblast growth factor, both ligands of tyrosine kinase receptors. Here, we examined the possibility that heparin inhibits signaling by thrombin and other activators of heterotrimeric G-proteins. DESIGN OF STUDY: Baboon aortic smooth muscle cells were stimulated with thrombin, angiotensin II, endothelin-1, and lysophosphatidic acid in the presence or absence of heparin. After stimulation, mitogen-activated protein kinase activity was measured with an in-gel phosphorylation assay, mitogen-activated protein kinase kinase-1 was immunoprecipitated from the same samples, and activity was measured with recombinant mitogen-activated protein kinase as a substrate. DNA synthesis was measured by 3H-thymidine labeling and scintillation counting. RESULTS: Heparin inhibited sustained activity of mitogen-activated protein kinase kinase-1 and mitogen-activated protein kinase and prevented DNA synthesis induced by thrombin, angiotensin II, endothelin-1, and lysophosphatidic acid. CONCLUSIONS: Heparin inhibits growth of baboon smooth muscle cells by preventing prolonged mitogen-activated protein kinase activation elicited by ligands of seven transmembrane domain receptors and heterotrimeric G-proteins. The results indicate that heparin interferes with a specific pathway in smooth muscle cell growth, which could be a future target in attempts to inhibit lesion development after vascular surgery.

Animals↗
PubMed2005

Human airway smooth muscle cells express the high affinity receptor for IgE (Fc epsilon RI): a critical role of Fc epsilon RI in human airway smooth muscle cell function.

Several reports suggest that activated airway smooth muscle (ASM) cells are capable of generating various proinflammatory mediators, including cytokines and chemokines. However, little is known about the mechanism involved in this process. In this regard, we have examined the expression and the role of the high affinity IgE receptor (Fc epsilonRI) by ASM cells. Human ASM cells were found to constitutively express transcripts coding for alpha, beta, and gamma subunits of Fc epsilonRI. Flow cytometry and Western blot analysis confirmed the expression of Fc epsilonRI alpha-chain protein. Interestingly, Fc epsilonRI alpha-chain immunoreactivity was also demonstrated in smooth muscle within bronchial biopsies of asthmatic subjects. Cross-linking of Fc epsilonRI induced mobilization of free calcium in ASM cells, one of the critical signals to trigger smooth muscle contraction. Furthermore, cultured ASM cells released IL-4, IL-13, IL-5, and eotaxin but not IFN-gamma, when sensitized with IgE followed by anti-IgE Ab cross-linking. The addition of anti-Fc epsilonRI alpha-chain Abs directed against IgE binding site inhibited this release. Taken together, these results suggest a potential new and important mechanism by which ASM cells may participate in airway inflammation and bronchoconstriction associated with allergic asthma.

Asthma↗
PubMed1999

Role of M2 muscarinic receptors in airway smooth muscle contraction.

Airway smooth muscle expresses both M2 and M3 muscarinic receptors with the majority of the receptors of the M2 subtype. Activation of M3 receptors, which couple to Gq, initiates contraction of airway smooth muscle while activation of M2 receptors, which couple to Gi, inhibits beta-adrenergic mediated relaxation. Increased sensitivity to intracellular Ca2+ is an important mechanism for agonist-induced contraction of airway smooth muscle but the signal transduction pathways involved are uncertain. We studied Ca2+ sensitization by acetylcholine (ACh) and endothelin-1 (ET-1) in porcine tracheal smooth muscle by measuring contractions at constant [Ca2+] in strips permeabilized with Staphylococcal alpha-toxin. Both ACh and ET-1 contracted airway smooth muscle at constant [Ca2+]. Pretreatment with pertussis toxin for 18-20 hours reduced ACh contractions, but had no effect on those of ET-1 or GTPgammaS. We conclude that the M2 muscarinic receptor contributes to airway smooth muscle contraction at constant [Ca2+] via the heterotrimeric G-protein Gi.

Acetylcholine↗
PubMed1992

Platelet-derived growth factor BB-dimer suppresses the expression of macrophage colony-stimulating factor in human vascular smooth muscle cells.

Vascular smooth muscle cell is a major cell component involved in the process of atherosclerosis. In the present study, we investigated the effects of platelet-derived growth factor (PDGF)-BB dimer on the expression of macrophage-colony stimulating factor (M-CSF) in vascular smooth muscle cells isolated from human umbilical artery. On Northern blot analysis of total RNAs isolated from smooth muscle cells, with human cDNA for M-CSF, a marked dose-dependent reduction of mRNA level was found in PDGF-BB-treated smooth muscle cells. Cellular production of M-CSF was estimated by immunoblot analysis of cell lysate with specific polyclonal antibody against recombinant human M-CSF. A concentration of 10 ng/ml PDGF-BB significantly reduced M-CSF mass in smooth muscle cells compared with that in the absence of PDGF-BB. These results suggest that PDGF-BB plays an important role in the cellular metabolism of vascular wall by regulating the rate of M-CSF production in vascular smooth muscle cells.

Antibodies↗
PubMedDate not supplied

Magnesium as a modifier of smooth muscle contractility.

In smooth muscle, Ca2+ enters the cell through two different types of Ca2+ channels, activates contractile filaments and induces contraction. These Ca2+ channels are inhibited by Ca2+ channel blockers and/or nitrocompounds. Mg2+ inhibits both of these Ca2+ channels and relaxes the muscle. A portion of the smooth muscle contraction is due also to the release of Ca2+ from the cellular storage site. Caffeine and norepinephrine release Ca2+ from this store to induce a transient contraction. The contraction induced by caffeine is greatly augmented in the absence of Mg2+. The other effect of Mg2+ deficiency is to inhibit the effects of various vasodilators. Vascular endothelium releases a substance which relaxes vascular smooth muscle and this relaxation is also inhibited by Mg2+ deficiency. Thus, Mg2+ has multiple sites and mechanisms of action in smooth muscle which remain to be clarified.

Animals↗
PubMed1999

Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation.

Airway smooth muscle proliferation is important in asthma and is dependent on pro- and antimitogenic factors and cell-matrix interactions. Here we show an antiproliferative effect of protease inhibitors on human airway smooth muscle due to inhibition of autocrine-derived matrix metalloproteinase (MMP)-2. Proliferation in response to fetal bovine serum, thrombin, and platelet-derived growth factor was inhibited by the broad-spectrum protease inhibitor Complete and the MMP inhibitors EDTA and Ro-31-9790 but not by cysteine or serine protease inhibitors. Conditioned medium from airway smooth muscle cells contained 72-kDa gelatinase that was secreted by growth-arrested cells and increased by fetal bovine serum but not by thrombin or platelet-derived growth factor. Immunostaining of cultured human airway smooth muscle cells and normal lung biopsies confirmed this gelatinase to be MMP-2. Our results suggest a novel role for MMP-2 as an important autocrine factor required for airway smooth muscle proliferation. Inhibition of MMPs could provide a target for the prevention of smooth muscle hyperplasia and airway remodeling in asthma.

Aprotinin↗
PubMed1996

Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation.

Smooth muscle cell proliferation and migration is important in arteriosclerosis. In this process, cytokines and growth factors are upregulated and bind to their respective receptors, which in turn stimulate mitogen-activated protein (MAP) kinases. MAP kinases then relay signals to the nucleus that activate quiescent smooth muscle cells. Phosphatases downregulate MAP kinases. We investigated the role of a dual-specificity tyrosine phosphatase, MAP kinase phosphatase-1 (MKP-1), in smooth muscle cell proliferation. MKP-1 expression was high in arterial tissue by Northern analysis, and MKP-1 message was detected mainly in the arterial smooth muscle layer by in situ hybridization. After balloon injury of the rat carotid artery, expression of MKP-1 decreased greatly, whereas that of MAP kinases, especially p44 MAP kinase, increased. The time course of the reduction in MKP-1 message correlated with increased tyrosine phosphorylation and elevated p44 MAP kinase enzymatic activity. In rat arterial smooth muscle cells overexpressing MKP-1, growth was arrested in the G1 phase and entry into the S phase was blocked. A reduction in MKP-1 expression may contribute in part to proliferation of smooth muscle cells after vascular injury, possibly through a decrease in dephosphorylation of p44 MAP kinase.

Angioplasty, Balloon↗
PubMed1995

Use of cultured airway myocytes for study of airway smooth muscle.

Cultured airway smooth muscle cells provide a convenient model system for studying the regulation of a wide range of airway responses at the cellular level. This review describes the characteristics of cultured airway smooth muscle cells and differences that exist between cultured cells and acutely dissociated cells or muscle strips. Receptor and ion-channel expression and control of coupling in cultured airway smooth muscle are reviewed. The methodology for airway smooth muscle culture is discussed. The main advantage of using cultured airway smooth muscle cells is that studies can be performed to examine long-term control of cell responses. Studies of the regulation of receptor expression and coupling, desensitization of receptor or channel-mediated responses, or regulation of the expression of important enzymes or muscle proteins can be readily performed in cell culture. In addition, cultured airway myocytes provide a useful secondary screening system for the development of novel therapeutic agents targeted at airway receptors that are expressed upon these cells.

Aged↗
PubMed1989

Effects of smooth muscle cell derived growth factor (SDGF) in combination with other growth factors on smooth muscle cells.

Recently intimal thickening was shown to be due to stimulation of proliferation of arterial smooth muscle cells (SMC) by autocrine secretion of growth factor(s). We have reported that cultured rabbit aortic SMC secrete a growth factor (SDGF) distinct from other known growth factors. This paper reports on studies on the biological characteristics of SDGF. Putative "competence" and "progression" growth factors synergistically stimulated DNA synthesis of cultured rabbit aortic SMC. Conditioned medium (CM) from SMC containing SDGF stimulated DNA synthesis in SMC synergistically with either the competence factors or the progression factors. This synergistic effect was also observed in the presence of optimal concentrations of both competence and progression factors. The continuous presence of CM was essential for its stimulation of DNA synthesis whereas the presence of PDGF for only the first 4 h of culture was sufficient to induce maximum stimulation of DNA synthesis. These results suggest that SDGF is a new growth factor distinct from either competence or progression factors and that it stimulates a different pathway in SMC from those stimulated by other known growth factors.

Animals↗
PubMed1975

[Studies of in vitro cultivated cells from the smooth muscle organs. 3. Effectiveness of some drugs on pulsation frequency of isolated smooth muscle cells of the chicken amnion].

The effects of some drugs on the beating frequency of isolated cells of the chick amnion cultivated on cover slips were investigated. Cholinergic and adrenergic agonists and antagonists, serotonine, antispasmodics, coronary dilatants and local anesthetics influenced the beating frequency significantly. The isolated chick amnion cells equal in their pharmacological behaviour the intact chick amnion and smooth muscle cells of mammals but differ from isolated beating heart cells.

Adrenergic beta-Antagonists↗