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PubMed2000

Molecular mechanisms for the regulation of penile smooth muscle contractility.

Relaxation of smooth muscle is viewed as a 'resetting' of contractile machinery and the resumption of a pre-contractile state is accomplished by lowering cytosolic Ca(2+) and/or by decreasing the sensitivity of the contractile machinery to Ca(2+). There are several mechanisms whereby cytosolic Ca(2+) can be reduced and relaxation achieved but, in general, all pathways depend upon the accumulation of cyclic nucleotides cAMP and cGMP or on the activation of K(+) channels resulting in hyperpolarization. Recently, activation of Na(+)/K(+) ATPase by nitric oxide has been shown to be involved in the relaxation of trabecular smooth muscle. Since Na(+)/K(+) ATPase is electrogenic, its stimulation would cause hyperpolarization and, in turn, would prevent the opening of voltage-dependent Ca(2+) channels. This manuscript briefly reviews the molecular mechanisms affected by muscle relaxants and vasodilators in the treatment of erectile dysfunction. International Journal of Impotence Research (2000) 12, Suppl 4, S34-S38.

Cyclic AMP↗

PubMed1989

Potassium depletion and regulation of angiotensin II receptors in vascular smooth muscle cells.

Mesenteric artery smooth muscle cells were grown in culture media containing high, normal, or low concentrations of potassium to study the effects on angiotensin II (Ang II) receptor regulation. Cell growth was similar among cells grown in the different culture media. Cells grown in high potassium media (K = 5.8 mEq/L) had an equilibrium dissociation constant, Kd, of 1.59 +/- 0.2 nM, whereas those grown in normal potassium media (K = 4.1 mEq/L) had a Kd of 1.79 +/- 0.2 nM and those grown in a low potassium media (K = 2.9 mEq/L) had a Kd of 1.19 +/- 0.12 nM (not significantly different, NS). Binding capacity of smooth muscle cells grown in high potassium media was 81 +/- 16.7 fmol/mg prot, 95.1 +/- 12.4 fmol/mg prot in those grown in normal potassium media and those grown in low potassium media 86.4 +/- 24.1 fmol/mg prot (NS). Binding of radiolabelled Ang II was reduced by approximately 70% in cells exposed to unlabelled Ang II for 30 or 60 minutes. However, this effect of exposure to Ang II to reduce subsequent binding of Ang II was identical in cells grown in high and low potassium medium. Therefore, we were unable to identify a direct effect of low potassium to induce changes in Ang II receptor binding affinity or binding capacity. Previously observed changes in these Ang II binding parameters in potassium-depleted rats was probably a consequence of other factors which were simultaneously altered by potassium deficiency.

Angiotensin II↗

PubMed2006

The antimicrobial peptide LL-37 enhances IL-8 release by human airway smooth muscle cells.

BACKGROUND: Human airway smooth muscle (HASM) cells release various chemokines that are involved in recruitment of inflammatory cells, which can be found within or in the vicinity of the airway smooth muscle layer in patients with inflammatory lung diseases. Inflammatory cells contain antimicrobial peptides including the cathelicidin LL-37 and neutrophil defensins (HNP1-3). OBJECTIVE: The aim of the study was to determine the effects of antimicrobial peptides on IL-8 (CXC chemokine ligand 8) release by HASM cells, and to study the underlying mechanisms. METHODS: Human airway smooth muscle cells were stimulated with LL-37 and HNP1-3, and IL-8 protein and mRNA levels were determined by sandwich ELISA and PCR. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was detected by using Western blot. RESULTS: LL-37 enhanced IL-8 release by HASM cells, which was dependent on ERK1/2 activation. Receptors known to be involved in LL-37-induced signaling, including the epidermal growth factor receptor and formyl peptide receptors, were not involved in LL-37 signaling in HASM cells. The purinergic receptor antagonist suramin did block LL-37-induced ERK1/2 phosphorylation and IL-8 release, and expression of mRNA for the purinergic receptor P2X(7) was detected in HASM cells. HNP1-3 did increase ERK1/2 phosphorylation, but did not enhance IL-8 release by HASM cells. CONCLUSION: These data show that HASM cells respond to the antimicrobial peptide LL-37 by releasing IL-8, suggesting that LL-37 is a regulator of the inflammatory process in various inflammatory lung diseases by enhancing IL-8 production. CLINICAL IMPLICATIONS: LL-37 released by inflammatory cells may amplify inflammation through induction of IL-8 release by airway smooth muscle.

Antimicrobial Cationic Peptides↗

PubMed1988

Comparison of fatty acid and triacylglycerol metabolism of macrophages and smooth muscle cells.

The response of macrophages and smooth muscle cells to culture in free fatty acid has been compared. Because oleate and linoleate promoted triacylglycerol enrichment of smooth muscle cells, whereas palmitate had little effect, oleate was used for these studies. The kinetics of the accumulation of triacylglycerol produced by oleate was comparable between smooth muscle cells and macrophages. When grown in increasing concentrations of oleic acid at various fatty acid to albumin molar ratios, the extent of triacylglycerol accumulation in both cell types was dependent on the concentration of oleate, the concentration of albumin, and the oleate to albumin molar ratio. However, macrophages contained 2.6-fold more triacylglycerol than smooth muscle cells in the presence of oleate at 0.36 mM or greater and at levels of albumin higher than 0.15 mM. The cellular triacylglycerol content of macrophages was linearly related to the oleate to albumin molar ratio at both a constant albumin concentration and a constant oleate concentration, whereas the accumulation of triacylglycerol in smooth muscle cells showed a curvilinear relationship. When cells were preloaded with triacylglycerol, smooth muscle cells showed a greater loss of lipid when exposed to albumin than macrophages did. Over a two-hr time period, macrophages incorporated twice as much labeled fatty acid as smooth muscle cells. Thus, while smooth muscle cells and macrophages showed similar responses to exogenous fatty acid and albumin, there were also significant quantitative distinctions.

Animals↗

PubMed2000

Cks1 mediates vascular smooth muscle cell polyploidization.

Vascular smooth muscle cells (VSMC) at capacitance arteries of hypertensive individuals and animals undergo dramatic polyploidization that contributes toward their hypertrophic phenotype. We report here the identification of a defective mitotic spindle cell cycle checkpoint in VSMC isolated from capacitance arteries of pre-hypertensive rats. These cells demonstrated a high predisposition to polyploidization in culture and failed to maintain cyclin B protein levels in response to colcemid, a mitotic inhibitor. Furthermore, this altered mitotic spindle checkpoint status was associated with the overexpression of Cks1, a Cdc2 adapter protein that promotes cyclin B degradation. Cks1 up-regulation, cyclin B down-regulation, and VSMC polyploidization were evidenced at the smooth muscle of capacitance arteries of genetically hypertensive and Goldblatt-operated rats. In addition, angiotensin II infusion dramatically increased Cks1 protein levels at capacitance arteries of normotensive rats, and angiotensin II treatment of isolated VSMC abrogated their ability to down-regulate Cks1 and maintain cyclin B protein expression in response to colcemid. Finally, transduction of VSMC from normotensive animals with a retrovirus that drives the expression of Cks1 was sufficient to alter their mitotic spindle cell cycle checkpoint status and promote unscheduled cyclin B metabolism, cell cycle re-entry, and polyploidization. These data demonstrate that Cks1 regulates cyclin B metabolism and ploidy in VSMC and may contribute to the understanding of the phenomena of VSMC polyploidization during hypertension.

Animals↗

PubMed1982

Intrafollicular pressure decreases in hamster preovulatory follicles during smooth muscle cell contraction in vitro.

Smooth muscle cells in the base of hamster follicles contract minutes prior to ovulation; during this contraction the profile of the follicle changes from low to tall. Our purpose was to measure intrafollicular pressure, independent of an intact circulatory system to the ovary, at the time when follicular smooth muscles are known to be contracting. Hamster ovaries were removed 13 hours after hCG injection and placed in a culture medium which supports in vitro ovulation. Intrafollicular pressure was measured continuously with a WPI Model 900 Micropressure system, while the follicle was being observed and photographed using a dissecting microscope and Zeiss 35 mm camera. Initial intrafollicular pressure was 2.1 +/- 1.1 mmHg (n = 47) in the absence of a blood supply. This pressure decreased slowly (0.03 mmHg/min.) until the transition from a low to tall profile occurred at which time the pressure decreased at a rate of 0.09 mmHg/min. At ovulation, the pressure drops precipitously to 0.0 mmHg. The condition of the follicle, in particular the apex, was examined using scanning electron microscopy (SEM). At 13 hours after hCG, rupture sites had started forming in the apices of 94.3% of the unovulated follicles. In some instances, surface epithelial cells were stretched apart and gaps were present between cells. More often portions of the surface epithelium were missing and the underlying cell layers were exposed. Fluid and erythrocytes were observed passing through the developing rupture sites. Taken together these observations demonstrate that intrafollicular pressure in hamster preovulatory follicles decreases gradually at the time follicular smooth muscle cells contract. We suggest that contraction of follicular SMC is a slow, gradual process which causes formation and/or enlargement of holes in the rupture site. An increase in the size or number of these apertures would lead to increased leakiness and could account for the observed acceleration in the rate of pressure decrease during profile transition. Our observations are the first to correlate changes in intrafollicular pressure with the contraction of smooth muscle cells and condition of the apex.

Animals↗

PubMed2003

The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation.

Vascular smooth muscle cells (VSMC) in mature, normal blood vessels exhibit a differentiated, quiescent, contractile morphology, but injury induces a phenotypic modulation toward a proliferative, dedifferentiated, migratory phenotype with upregulated extracellular matrix protein synthesis (synthetic phenotype), which contributes to intimal hyperplasia. The mTOR (the mammalian target of rapamycin) pathway inhibitor rapamycin inhibits intimal hyperplasia in animal models and in human clinical trials. We report that rapamycin treatment induces differentiation in cultured synthetic phenotype VSMC from multiple species. VSMC treated with rapamycin assumed a contractile morphology, quantitatively reflected by a 67% decrease in cell area. Total protein and collagen synthesis were also inhibited by rapamycin. Rapamycin induced expression of the VSMC differentiation marker contractile proteins smooth muscle (SM) alpha-actin, calponin, and SM myosin heavy chain (SM-MHC), as observed by immunoblotting and immunohistochemistry. Notably, we detected a striking rapamycin induction of calponin and SM-MHC mRNA, suggesting a role for mTOR in transcriptional control of VSMC gene expression. Rapamycin also induced expression of the cyclin-dependent kinase inhibitors p21(cip) and p27(kip), consistent with cell cycle withdrawal. Rapamycin inhibits mTOR, a signaling protein that regulates protein synthesis effectors, including p70 S6K1. Overexpression of p70 S6K1 inhibited rapamycin-induced contractile protein and p21(cip) expression, suggesting that this kinase opposes VSMC differentiation. In conclusion, we report that regulation of VSMC differentiation is a novel function of the rapamycin-sensitive mTOR signaling pathway.

Animals↗

PubMed1996

Change in intramural strain distribution in rat aorta due to smooth muscle contraction and relaxation.

Effect of smooth muscle contraction on intramural strain distribution in rat thoracic aorta was investigated with residual strain considered. Short segments sliced from the aortas were cut radially to release residual strain in an aerated Krebs-Ringer solution (37 degrees C). Each segment opened up immediately to form an arc. Opening angle was measured at this point and after smooth muscle contraction and relaxation. The angle increased from 97 +/- 11 degrees (means +/- SE, n = 14) to 153 +/- 14 degrees with the contraction and decreased to 68 +/- 9 degrees with the relaxation, indicating increase in residual strain with smooth muscle contraction. Intramural strain distribution at various pressures was calculated from the opening angle and pressure-diameter relations of the aortas. Strain distribution was almost uniform at 55 mmHg under smooth muscle relaxation, whereas this pressure exceeded 200 mmHg because of the increase in residual strain and decrease in vessel diameter under smooth muscle contraction. These results suggest aortic smooth muscle may change its contractile state through myogenic response to keep intramural strain distribution uniform against temporary change in blood pressure and thus maintain mechanical homeostasis in the aortic wall.

Animals↗

PubMed1990

Phosphoinositide metabolism in airway smooth muscle.

Contraction of airway smooth muscle (ASM) results from an increase in cytoplasmic free Ca2+ and appears to be independent of changes in membrane potential or the presence of extracellular Ca2+. Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), the product of receptor-mediated hydrolysis of a membrane phosphoinositide, phosphatidylinositol 4,5-bisphosphate, is capable of releasing Ca2+ from intracellular stores in this tissue and has been proposed as the intracellular second messenger responsible for agonist-induced changes in cytosolic Ca2+ and hence contraction. In this report, we discuss the evidence for this signaling system in ASM and present new data on mass changes in Ins(1,4,5)P3 in carbachol-stimulated bovine tracheal smooth muscle. The rapid, transient accumulation of this second messenger in ASM is thought to reflect regulation of the enzymes involved in the metabolism rather than the synthesis of this inositol polyphosphate. The potential mechanisms of this regulation are discussed in relation to the initiation and maintenance of contraction in ASM.

Animals↗

PubMed1985

Production and release of inactive renin by human vascular smooth muscle cells.

Human arterial smooth muscle cells were obtained from surgically excised tissues and cultured by the explant method. The cultured cells had both active and inactive forms of an angiotensin I forming enzyme. About a five-fold increase in the activity was obtained by trypsin treatment. This renin-like enzyme was also found in abundance in the culture media, mostly in an inactive form. Most of the enzyme activity, either before or after the activation, was suppressed by an antibody specific to human renin. The inactive enzyme was activated to some extent also by acidification and by cold exposure. The molecular weight of the inactive enzyme was estimated to be approximately 49,000 by gel filtration. These results suggest that human vascular smooth muscle cells can produce renin and release an inactive form of renin, and can be a potential source of plasma inactive renin under certain conditions such as the anephric state.

Angiotensin I↗

PubMed1995

Structure-function relationships in smooth muscle: the missing links.

Smooth muscle cells have developed a contractile machinery that allows them to exert tension on the surrounding extracellular matrix over their entire length. This has been achieved by coupling obliquely organized contractile filaments to a more-or-less longitudinal framework of cytoskeletal elements. Earlier structural data suggested that the cytoskeleton was composed primarily of intermediate filaments and played only a passive role. More recent findings highlight the segregation of actin isotypes and of actin-associated proteins between the contractile and cytoskeletal domains and raise the possibility that the cytoskeleton performs a more active function. Current efforts focus on defining the relative contributions of myosin cross-bridge cycling and actin-associated protein interactions to the maintenance of tension in smooth muscle tissue.

Cytoskeleton↗

PubMed1991

Effect of serotonin on intracellular free calcium of rat cerebrovascular smooth muscle cells in culture.

Smooth muscle cells were dissociated from conducting cerebral arteries of adult rats and maintained in culture for 2-4 days. The calcium-sensitive fluorescent probe, fura-2, was used to study the effect of the vasoconstrictor serotonin (5-HT) on the level of free intracellular Ca2+ in these cells. The baseline level of free intracellular calcium was 39 +/- 3.6 nM. In 74 out of 110 cells, 5-HT application transiently increased the free Ca2+ content. This effect was dose-dependent and was suppressed by nanomolar concentrations of the 5-HT2 receptor antagonist, ketanserin. The 5-HT induced rise in free intracellular calcium was not prevented by the presence of Co2+, La3+, or nifedipine, blockers of voltage-sensitive calcium channels. These results indicate that 5-HT mobilizes intracellular Ca2+ in cultured smooth muscle cells derived from the rat cerebrovasculature. The mobilization of intracellular Ca2+ appears to be triggered by a 5-HT2 type receptor, although further pharmacological experiments are required to verify this hypothesis.

Animals↗

PubMed1987

Cyclic AMP inhibits increased collagen production by cyclically stretched smooth muscle cells.

Rabbit arterial smooth muscle cells, grown on elastin membranes which were cyclically elongated and relaxed, responded by increasing their rates of synthesis of protein and, in particular, of collagen, compared to stationary controls. Raising intracellular cyclic AMP (cAMP) levels by adding theophylline or dibutyryl cAMP to the culture medium prevented the synthetic response to cyclic stretching, but did not alter the rates of protein or collagen synthesis by stationary controls. Both synthesis and degradation of collagen by cyclically stretched cells increased in parallel such that the proportion of synthesized collagen that was degraded was similar to that found in the stationary cultures. Collagen degradation was not affected by theophylline administration to stationary cell cultures but the drug increased degradation of collagen by cyclically stretched cells. We conclude that the net production of protein, and in particular of a structural protein, collagen, by arterial smooth muscle cells subjected to the mechanical force of stretching was inhibited when intracellular levels of cAMP were raised. The results suggest that cAMP may play a role in the modulation of structural protein content of artery walls in response to changes in tensile stress.

Animals↗

PubMed1989

Heterologous regulation of EGF receptor function in cultured aortic smooth muscle cells.

A10 cultured smooth muscle cells from rat embryonic thoracic aorta bound 125I-labelled epidermal growth factor (125I-EGF), and responded to EGF by an increase in DNA synthesis. Scatchard analysis of binding data obtained at 4 degrees C showed curvilinearity consistent with there being two affinity classes of binding site. The amount of 125I-EGF that bound was decreased by treatment of the A10 cells at 37 degrees C with [Arg8]vasopressin or with 5-hydroxytryptamine (5-HT). Scatchard analysis of binding (at 4 degrees C after pretreatment at 37 degrees C) revealed this effect to be due to a loss of the high-affinity component of 125I-EGF binding, with no change in total receptor number. The presence of vasopressin or 5-HT raised the concentration of EGF required for the stimulation of DNA synthesis. Cultured A10 aortic smooth muscle cells therefore have receptors for EGF that mediate an increase in cell proliferation. EGF receptor function is modified by vasopressin and 5-HT, probably as a consequence of their effects on EGF receptor affinity.

Animals↗

PubMed2002

Adenovirus-mediated overexpression of a cyclin-dependent kinase inhibitor, p57Kip2, suppressed vascular smooth muscle cell proliferation.

Vascular smooth muscle cell (VSMC) proliferation after arterial injury is playing a pivotal role in the pathogenesis of a number of vascular proliferative disorders including atherosclerosis and restenosis after balloon-mediated angioplasty. Thus, a better understanding of the molecular mechanisms underlying VSMC proliferation in response to injury would have important therapeutic implications. Cell proliferation is controlled by an intricate network of extracellular and intracellular signaling pathways which are processing various growth regulatory signals and integrating them into the basic cell-cycle regulatory machinery through control of cyclin dependent kinases (CDK). CDK are positively regulated by cyclins and negatively regulated by CDK inhibitory proteins (CKI). To dissect the role of CKI in VSMC proliferation, we prepared the replication-deficient adenovirus constructs expressing p21 family members (Ad-CKI), p21Waf1, p27Kip1 and p57Kip2, respectively, and investigated the effect of CKI overexpression on the proliferation of vascular smooth muscle cells. The overexpression of each CKI protein in cultured VSMC was confirmed by western blot analysis. Flowcytometric analysis revealed that the Ad-CKI infected VSMC were largely retained in G1 phase, and had significantly less G2/M fraction than control cells. The extent of DNA synthesis in VSMC was assessed by [3H]-thymidine uptake, and shown to be inhibited by Ad-CKI dose dependently. Among three CKIs tested in this study, p57Kip2 showed the most significant suppression of DNA synthesis. In order to investigate in vivo effect of p57Kip2 overexpression, Ad-p57 was locally delivered to the luminal wall of rabbit carotid arteries after balloon angioplasty. Histological examinations revealed that the local infection of Ad-p57 significantly suppressed the neointimal formation at the site of vascular injury. These results clearly demonstrated the antiproliferative role of p57Kip2 in VSMC, and also proposed a possibility of gene therapy approach for vascular proliferative disorders.

Adenoviridae↗

PubMed1996

Stimulation of sodium pump by vasoactive intestinal peptide in guinea-pig isolated trachea: potential contribution to mechanisms underlying relaxation of smooth muscle.

1. Relaxation of airway smooth muscle induced by vasoactive intestinal peptide (VIP) is mediated by adenosine 3':5' cyclic monophosphate (cyclic AMP). An interaction between the synthesis of cyclic AMP and enzymic activity of the plasmalemmal sodium pump (Na(+)-K(+)-ATPase) exists in certain isolated cell systems. This study sought to determine the contribution of Na(+)-K(+)-ATPase activity to relaxation of airway smooth muscle evoked by VIP. 2. All experiments were performed on isolated strips of guinea-pig trachea from which the epithelium had been removed. VIP was a more potent relaxant in tissues that were contracted with carbachol than those contracted with an equi-effective depolarizing concentration of K+. 3. Ouabain (0.1 microM-10 microM) induced contraction of tracheal strips. Contraction to ouabain (5 microM) was abolished following incubation of tissues with K(+)-free, or Ca(2+)-free (+ EGTA, 0.1 mM) physiological solutions. The contractile response to ouabain (5 microM) was not influenced significantly by exposure of the tissues to atropine (1 microM), phentolamine (5 microM) and diphenhydramine (1 microM) for 60 min. 4. Tissues were incubated with ouabain (5 microM; 60 min) or K(+)-free physiological solution (60 min) to inhibit Na(+)-K(+)-ATPase activity. These procedures reduced relaxation induced by VIP, peptide histidine isoleucine, forskolin, isoprenaline and sodium nitroprusside. 5. Relaxation to VIP was impaired significantly following exposure of tissues to a low Na+ solution (30 min) or amiloride (500 microM; 30 min). 6. Ouabain-sensitive uptake of 86Rb was measured in tracheal strips (devoid of epithelium and cartilage) as an index of Na(+)-K(+)-ATPase activity. VIP (1 microM; 2 min) caused a 4.7 fold stimulation of ouabain-sensitive uptake of 86Rb. This effect was impaired significantly by low Na+ solution. 7. The results suggest that (i) relaxation of tracheal smooth muscle to VIP is sensitive to procedures that inhibit activity of Na(+)-K(+)-ATPase and invoke a role for altered sodium pump function in the mechanisms that underlie cyclic AMP-dependent relaxation; and (ii) VIP stimulates ouabain-sensitive uptake of 86Rb in airway smooth muscle in a Na(+)-dependent manner.

Animals↗

PubMed1986

Increased activity of chondroitin sulfate-synthesizing enzymes during proliferation of arterial smooth muscle cells.

Cultured arterial smooth muscle cells incorporate [35S]sulfate into the extracellular chondroitin sulfate/dermatan sulfate containing proteoglycans at a higher rate in the phase of logarithmic growth than do non-dividing cells. The cell growth-dependent decrease in 35S incorporation with increasing cell density is accompanied by a decrease in the activity of chondroitin sulfate-synthesizing enzymes. The specific activity of xylosyl transferase, N-acetylgalactosaminyl transferase I and chondroitin sulfotransferase declines as the cells proceed from low to high densities. The corresponding correlation coefficients are 0.86, 0.91 and 0.89. The ratio of C-6OH/C-4OH sulfation of chondroitin shows a cell proliferation-dependent decrease indicating an inverse correlation of chondroitin 6-sulfotransferase and chondroitin 4-sulfotransferase activity. The observed changes in the expression of enzyme activities are thought to have some implications in the pathogenesis of arteriosclerosis, the initial stages of which are characterized by proliferation of arterial smooth muscle cells.

Animals↗

PubMed1981

Phenotype-dependent response of cultured aortic smooth muscle to serum mitogens.

Smooth muscle cells from the aortic media of adult pigs and monkeys have been grown in primary culture by plating cells enzymatically dissociated from the intact aorta. During the first 6 d these cells are in the "contractile" phenotype. That is, they contract slowly in response to angiotensin II and their cytoplasm is filled with both thick and thin myofilaments. In this state they do not incorporate [3H]thymidine into DNA or proliferate in response to normolipemic or hyperlipemic whole blood serum (WBS). After 7 d in culture the cells undergo a spontaneous modulation of phenotype to a "synthetic" state where they cannot be stimulated to contract and their cytoplasm is filled with organelles usually associated with synthesis of secretory protein. Thick myosin-containing filaments can no longer be demonstrated. When challenged with normolipemic or hyperlipemic WBS the cells incorporate [3H]thymidine into DNA and undergo logarithmic growth. It is suggested that when smooth muscle is the contractile phenotype (as normally exists for most cells in the aortic media of adult animals) it does not divide when challenged with serum mitogens but can undergo a change of phenotype to a synthetic state in which division can be stimulated.

Animals↗