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PubMed1984

Effects of magnesium chloride on smooth muscle actomyosin adenosine-5'-triphosphatase activity, myosin conformation, and tension development in glycerinated smooth muscle fibers.

The contractile system of smooth muscle exhibits distinctive responses to varying Mg2+ concentrations in that maximum adenosine-5'-triphosphatase (ATPase) activity of actomyosin requires relatively high concentrations of Mg2+ and also that tension in skinned smooth muscle fibers can be induced in the absence of Ca2+ by high Mg2+ concentrations. We have examined the effects of MgCl2 on actomyosin ATPase activity and on tension development in skinned gizzard fibers and suggest that the MgCl2-induced changes may be correlated to shifts in myosin conformation. At low concentrations of free Mg2+ (less than or equal to 1 mM) the actin-activated ATPase activity of phosphorylated turkey gizzard myosin is reduced and is increased as the Mg2+ concentration is raised. The increase in Mg2+ (over a range of 1-10 mM added MgCl2) induces the conversion of 10S phosphorylated myosin to the 6S form, and it was found that the proportion of myosin as 10S is inversely related to the level of actin-activated ATPase activity. Activation of the actin-activated ATPase activity also occurs with dephosphorylated myosin but at higher MgCl2 concentrations, between 10 and 40 mM added MgCl2. Viscosity and fluorescence measurements indicate that increasing Mg2+ levels over this concentration range favor the formation of the 6S conformation of dephosphorylated myosin, and it is proposed that the 10S to 6S transition is a prerequisite for the observed activation of ATPase activity. With glycerinated chicken gizzard fibers high MgCl2 concentrations (6-20 mM) promote tension in the absence of Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Actomyosin↗
PubMed2005

Induction of smooth muscle cell-like phenotype in marrow-derived cells among regenerating urinary bladder smooth muscle cells.

Tissue regeneration on acellular matrix grafts has great potential for therapeutic organ reconstruction. However, hollow organs such as the bladder require smooth muscle cell regeneration, the mechanisms of which are not well defined. We investigated the mechanisms by which bone marrow cells participate in smooth muscle formation during urinary bladder regeneration, using in vivo and in vitro model systems. In vivo bone marrow cells expressing green fluorescent protein were transplanted into lethally irradiated rats. Eight weeks following transplantation, bladder domes of the rats were replaced with bladder acellular matrix grafts. Two weeks after operation transplanted marrow cells repopulated the graft, as evidenced by detection of fluorescent staining. By 12 weeks they reconstituted the smooth muscle layer, with native smooth muscle cells (SMC) infiltrating the graft. In vitro, the differential effects of distinct growth factor environments created by either bladder urothelial cells or bladder SMC on phenotypic changes of marrow cells were examined. First, supernatants of cultured bladder cells were used as conditioned media for marrow cells. Second, these conditions were reconstituted with exogenous growth factors. In each case, a growth factor milieu characteristic of SMC induced an SMC-like phenotype in marrow cells, whereas that of urothelial cells failed. These findings suggest that marrow cells differentiate into smooth muscle on acellular matrix grafts in response to the environment created by SMC.

Animals↗
PubMed1990

Regulation of alpha-smooth muscle actin and other polypeptides in proliferating and density-arrested vascular smooth muscle cells.

We have examined alpha-smooth muscle actin (alpha-SM actin) protein and mRNA levels in proliferating and density-arrested rabbit vascular smooth muscle cells (SMC) and also studied overall polypeptide synthesis in these cells by two-dimensional (2-D) gel electrophoresis. Of the approximately 1,000 cellular polypeptides resolved by 2-D gel analysis, we consistently detected increased expression of 12 polypeptides in growth-arrested SMC. These polypeptides, with apparent molecular weights of 24,000 to 55,000 exhibited relative increases of between fourfold to greater than tenfold. Three of these polypeptides were expressed at undetectable levels in proliferating SMC. We also detected 12 secreted polypeptides that were expressed at higher levels in growth-arrested SMC. More changes were associated with the secreted polypeptides, since they represented approximately 4% of the total resolved secreted polypeptides, while only 1% of the cellular polypeptides were increased in high-density growth-arrested cells. Under these conditions we observed no change in relative alpha-SM actin protein content as determined by 2-D gel analysis and Western blots. This was corroborated by high levels of alpha-SM actin mRNA levels in both proliferating and high-density growth-arrested SMC. These results indicate rabbit vascular SMC maintain a high level of expression of a smooth muscle differentiation marker (alpha-SM actin) in a proliferation- and density-independent manner. We also examined polypeptide synthesis in SMC isolated by enzymatic digestion of the aorta vs. cells isolated by the explant method. We found that although overall protein patterns were remarkably similar, several differences were observed. These differences were not due to increased contamination by fibroblasts, since both enzymatically- and explant-derived SMC contained high levels of alpha-SM actin as determined by immunofluorescence and by Northern analysis.

Actins↗
PubMed1977

Distinction between smooth muscle, fibroblasts and endothelial cells in culture by the use of fluoresceinated antibodies against smooth muscle actin.

FITC-labelled antibodies against native actin from chicken gizzard smooth muscle (Gröschel-Stewart et al., 1976) have been used to stain cultures of guinea-pig vas deferens and taenia coli, rabbit thoracic aorta, rat ventricle and chick skeletal muscle. The I-band of myofibrils of cardiac muscle cells and skeletal muscle myotubes stains intensely. In isolated smooth muscle cells, the staining is located exclusively on long, straight, non-interrupted fibrils which almost fill the cell. Smooth muscle cells which have undergone morphological "dedifferentiation" to resemble fibroblasts with both phase-contrast microscopy and electronmicroscopy still stain intensely with the actin antibody. In those muscle cultures which contain some fibroblasts or endothelial cells, the non-muscle cells are not stained with the actin antibody even when the reactions are carried out at 37 degrees C for 1 h or after glycerination. Prefusion skeletal muscle myoblasts also do not stain with this antibody. It is concluded that the actin antibody described in this report is directed against a particular sequence of amino acids in muscle actin which is not homologous with non-muscle actin. The usefulness of this antibody in determining the origin of cells in certain pathological conditions such as atherosclerosis is discussed.

Actins↗
PubMed2002

Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy.

The insulin-like growth factor-binding protein 4 (IGFBP-4), the most abundant IGF-binding protein produced by rodent smooth muscle cells (SMC), is degraded by specific protease(s) potentially releasing IGF-I for local bioactivity. IGFBP-4 protease(s) recognizes basic residues within the midregion of the molecule. We constructed a mutant IGFBP-4 with the cleavage domain substitution 119-KHMAKVRDRSKMK-133 to 119-AAMAAVADASAMA-133. Myc-tagged native and IGFBP-4.7A retained equivalent IGF-I binding affinity. Whereas native IGFBP-4 was cleaved by SMC-conditioned medium, IGFBP-4.7A was completely resistant to proteolysis. To explore the function of the protease-resistant IGFBP-4 in vivo, expression of the mutant and native proteins was targeted to SMC of transgenic mice by means of a smooth muscle alpha-actin promoter. Transgene expression was confined to SMC-rich tissues in all lines. Bladder and aortic immunoreactive IGFBP-4/transgene mRNA ratios in SMP8-BP4.7A mice were increased by 2- to 4-fold relative to SMP8-BP4 mice, indicating that the IGFBP-4.7A protein was stabilized in vivo. SMP8-BP4.7A mice had lower aortic, bladder, and stomach weight and intestinal length relative to SMP8-BP4 counterparts matched for protein expression by Western blotting. Thus, IGFBP-4.7A results in greater growth inhibition than equivalent levels of native IGFBP-4 in vivo, demonstrating a role for IGFBP-4 proteolysis in the regulation of IGF-I action.

Alanine↗
PubMed2006

Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia.

BACKGROUND: The mechanism of pulmonary artery smooth muscle cell (PA-SMC) hyperplasia in idiopathic pulmonary artery hypertension (iPH) may involve both an inherent characteristic of PA-SMCs and abnormal control by external stimuli. We investigated the role of pulmonary microvascular endothelial cells (P-ECs) in controlling PA-SMC growth. METHODS AND RESULTS: Serum-free medium of quiescent P-ECs elicited marked PA-SMC proliferation, and this effect was greater with P-ECs from patients with iPH than from control subjects and greater with PA-SMCs from these patients than from control subjects. Fluoxetine, which inhibits serotonin-induced mitogenesis by blocking the serotonin transporter, and p-chlorophenylalanine, which inhibits serotonin synthesis by blocking tryptophan hydroxylase (TPH), caused a similar 60% reduction in the growth-promoting effect of P-EC media, whereas endothelin receptor blockers had no effect. Assays of TPH activity in P-EC medium based on p-chlorophenylalanine-sensitive 5-hydroxytryptophan accumulation or serotonin determination indicated serotonin synthesis by P-ECs and an increase in this TPH-dependent process in iPH. Expression of the tph1 gene encoding the peripheral form of the TPH enzyme was increased in lungs and P-ECs from patients with iPH. Lung TPH1 immunostaining was confined to the pulmonary vessel intima. CONCLUSIONS: P-ECs produce paracrine factors governing PA-SMC growth. Serotonin, the main P-EC-derived growth factor, is overproduced in iPH and contributes to PA-SMC hyperplasia.

Aged↗
PubMed1990

Phenotypic expression of surface antigens of rabbit aortic smooth muscle cells in culture. Monoclonal antibody, 2P1A2, characteristic of smooth muscle cells present in atherosclerotic plaque, is not correlated with cell proliferation.

The expression of smooth muscle cell (SMC) antigens was studied in culture by immunofluorescence and immunoelectron microscopy. As specific SMC markers, we used 2 monoclonal antibodies (MAb), 1PC1 and 2P1A2 which are able to detect atherosclerotic plaques in the rabbit. MAb 1PC1 recognizes an antigen expressed on the cell surface, starting on the 7th day in primary culture after serum activation, and then secreted. On a confluent SMC monolayers this antigen appears outside the cell as an important filamentous network. The kinetics of secretion of this external protein recognized by 1PC1 corresponds to the kinetics of the secretory phenotype described by Chamley-Campbell and Campbell (Atherosclerosis, 40 (1981) 347). 2P1A2 MAb is specific for SMCs exclusively present in the rabbit atherosclerotic plaque. We studied the degree of reactivity of 2P1A2 with SMCs during primary cell culture. This "atherosclerotic" antigen of SMCs recognized by 2P1A2 is expressed in culture conditions by SMCs from rabbit normal media. This antigen appears after 3 days of serum activation, and heparin growth inhibition does not interfere with its expression. 2P1A2 recognized antigen is expressed during all cell cycle phases without amplification. 3 days after fetal calf serum (FCS) stimulation of cells which are in G0/G1, 89% are labelled by 2P1A2, 4 days later G0/G1 positive cells constitute 49%. We conclude that 2P1A2 immunolabelling on the SMC surface reflects an activated state which is not correlated with SMC proliferation.

Animals↗
PubMed1998

Smooth muscle cell heterogeneity: patterns of gene expression in vascular smooth muscle cells in vitro and in vivo.

Early morphological and biochemical studies indicated that vascular smooth muscle cells (VSMCs) exhibited two distinct phenotypes and that a change from the contractile to the synthetic phenotype was a prerequisite for progression of vascular disease. More recently, it has become evident that these phenotypes probably represent the extremes of a spectrum of phenotypes that may coexist in the vessel wall, which are dictated by their environment and functional requirements and which reflect differing patterns of gene expression. Therefore, knowledge of the key factors that regulate these patterns of gene expression is likely to lead to the ability to manipulate VSMC phenotype. However, before such factors can be identified, the relationship between VSMC gene expression and VSMC phenotype must first be established. We therefore undertook a differential screen of cDNA from VSMCs in vitro to provide a bank of gene markers that could be used under a variety of circumstances to define VSMC phenotype in terms of the pattern of genes expressed. Using this approach, we have found that the pattern of gene expression that occurs during neointima formation in the balloon-injured rat carotid artery is very similar to that seen at a specific period in the developing aorta of the early neonate and is characterized by coexpression of genes for both contractile and matrix proteins. Furthermore, recent studies have shown that VSMCs isolated at different stages of aortic development can stably maintain different phenotypic characteristics in cell culture. The use of these cells in transfection experiments with SM-specific promoter-chloramphenicol acetyltransferase reporter constructs may enable us to determine what regulates the pattern of gene expression in different VSMC phenotypes. Such studies may ultimately lead to the identification of transcription factors responsible for determining VSMC phenotype and may therefore provide targets for therapy aimed at manipulating VSMC gene expression in vascular disease.

Animals↗
PubMed1997

A 260-kDa filamin/ABP-related protein in chicken gizzard smooth muscle cells is a new component of the dense plaques and dense bodies of smooth muscle.

A 260-kDa protein, termed cgABP260, which localized in the dense plaques and dense bodies of smooth muscle cells, was found in a low-salt alkaline extract of chicken gizzard smooth muscle. An antibody against cgABP260 was used to screen a chicken gizzard cDNA library, and the nucleotide sequence of the partial cDNA encoding this protein was determined. Comparison of predicted amino acid sequences revealed that the protein had significant homology with human ABP-280 and chicken retina filamin [Barry, C.P. et al. (1993) J. Biol. Chem. 268, 25577-25586], but despite the high homology, cgABP260 was immunologically distinguishable from filamin. Immunoblot analysis showed that an anti-cgABP260 antibody reacted exclusively with the cgABP260 band of smooth, skeletal, and cardiac muscle tissues. By indirect immunofluorescence, the membrane-affinity-purified antibody against cgABP260 intensely stained the dense plaques of the isolated smooth muscle cells. Immunoelectron microscopy showed that immunogold particles representing cgABP260 were found abundantly on the dense plaques and less abundantly on the dense bodies. Its amino acid sequence, molecular size, immunological reactivity, and localization in smooth muscle thus indicated that cgABP260 is a new component of the dense plaques and dense bodies of smooth muscle cells.

Amino Acid Sequence↗
PubMed1986

Limited proteolytic digestion and dissociation of smooth muscle phosphatase-I modifies its substrate specificity. Preparation and properties of different forms of smooth muscle phosphatase-I.

Smooth muscle phosphatase-I (SMP-I), a protein phosphatase purified from turkey gizzard smooth muscle, is composed of 2 regulatory subunits (Mr = 60,000 and 55,000) and a catalytic subunit (Mr = 38,000). Two other forms of this enzyme have been prepared and characterized. The free catalytic subunit, termed SMP-Ic, was prepared by ethanol treatment of SMP-I, and a form devoid of the 55,000-Da subunit, termed SMP-I2, was prepared by limited tryptic digestion. Exposure of SMP-I to proteases like trypsin and chymotrypsin results in a rapid degradation of the 55,000-Da polypeptide. Degradation of the catalytic subunit is observed only upon prolonged digestion. The 60,000-Da polypeptide appears to be resistant to the action of trypsin and chymotrypsin. SMP-I dephosphorylates myosin light chains but is not active toward intact myosin or heavy meromyosin. However, when the catalytic subunit is dissociated from both regulatory subunits or from the 55,000-Da polypeptide, the enzyme becomes active toward myosin suggesting that the 55,000-Da polypeptide inhibits the activity of the catalytic subunit toward myosin. In addition to alteration of the substrate specificity, the regulatory subunits also modulate the effect of divalent cations, like Mn2+, on the activity of the enzyme.

Animals↗
PubMed1991

Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation.

Mesangial cell proliferation is common in glomerulonephritis but it is unclear if proliferation is associated with any in vivo alteration in phenotype. We investigated whether mesangial of mesangial proliferative nephritis induced with antibody to the Thy-1 antigen present on mesangial cells. At day 3 glomeruli displayed de novo immunostaining for alpha-smooth muscle actin in a mesangial pattern, correlating with the onset of proliferation, and persisting until day 14. An increase in desmin and vimentin in mesangial regions was also noted. Immunoelectron microscopy confirmed that the actin-positive cells were mesangial cells, and double immunolabeling demonstrated that the smooth muscle actin-positive cells were actively proliferating. Northern analysis of isolated glomerular RNA confirmed an increase in alpha and beta/gamma actin mRNA at days 3 and 5. Complement depletion or platelet depletion prevented or reduced proliferation, respectively; these maneuvers also prevented smooth muscle actin and actin gene expression. Studies of five other experimental models of nephritis confirmed that smooth muscle actin expression is a marker for mesangial cell injury. Thus, mesangial cell proliferation in glomerulonephritis in the rat is associated with a distinct phenotypic change in which mesangial cell assume smooth muscle cell characteristics.

Actins↗
PubMed1997

Disruption of integrin alpha 5 beta 1 signaling does not impair PDGF-BB-mediated stimulation of the extracellular signal-regulated kinase pathway in smooth muscle cells.

Smooth muscle cell (SMC) proliferation is dependent on both anchorage to the extracellular matrix by integrins and the presence of growth factors. Integrins and growth factor receptors transduce signals that seem to converge on the extracellular signal-regulated (ERK) pathway, but the molecular basis for this interaction is not known. SMC proliferation has previously been shown to be supported by culture on fibronectin (FN), whereas cells cultured on laminin (LN) are growth inhibited. In the present study, we examined the mitogenic response to platelet-derived growth factor BB (PDGF-BB) in baboon SMCs cultured on FN vs. LN. Induction of DNA synthesis and the activity of ERK and the ERK activating kinase MKK-1 were reduced only slightly after stimulation with PDGF-BB in cells cultured on LN vs. those cultured on FN. We tested the possibility that endogenous FN secretion contributes to the ability of the cells to respond to PDGF stimulation during culture on LN. Inhibition of interactions between FN and integrin alpha 5 beta 1 by the competitive GRGDSP-peptide or anti-alpha 5 integrin antibody restricted cell spreading, reduced cell-surface staining for alpha 5 beta 1 and FN fibrils, and inhibited PDGF-BB-induced DNA synthesis. These results showed that SMC growth on LN required a provisional FN matrix. Although disruption of interactions between alpha 5 beta 1 and FN by the GRGDSP-peptide prevented PDGF-BB-induced DNA synthesis, neither ERK activity nor translocation of ERKs into the nucleus was inhibited. These results show that integrins regulate SMC growth through pathways that function in parallel with, but distinct from, growth factor-mediated ERK signaling.

Animals↗
PubMed1982

In vitro ovulation of hamster oocytes depends on contraction of follicular smooth muscle cells.

Smooth muscle cells (SMC) of the hamster follicle contract prior to ovulation, and their contraction produces a V-shaped constriction in the base of the follicle. We have determined when basal constrictions first appear in follicles removed from females at various preovulatory times by examining stained, thick sections with a brightfield microscope. The time to ovulation was controlled by injecting the female with human chorionic gonadotropin (hCG). The shape of the follicle was classified as flat, small V, medium V, or large V depending on the size of the basal constriction. Twenty-nine out of 30 follicles removed 12 hours after the hCG injection had flat bases or small V-shaped constrictions. However, by 12.5 and 13.0 hours after hCG injection, 45 and 54%, respectively, of the follicles had medium and large V-shaped constrictions in their bases. Transmission electron microscopy was used to confirm that flat follicles had uncontracted SMC, follicles with small V's had uncontracted or slightly contracted SMC, and follicles with medium and large V's had highly contracted SMC. When 12 hour follicles were removed from females and cultured in vitro, ovulation did not occur. Microscopic examinations showed that SMC had not contracted in these follicles during culture. Some (36.6%) 12.5 hour follicles and most (69.9%) 13 hour follicles ovulated when cultured in vitro. The majority of those which failed to do so, did not have contracted SMCs. We interpret these data to mean that in hamsters follicular SMC begin to contract in some follicles between 12-12.5 hours after the hCG injection. If contraction has begun in vivo, then the ovary may be removed from the female and ovulation will occur during in vitro culture. If contraction has not begun in vivo, it will not do so using the in vitro conditions described in this study and ovulation will not occur. These observations are consistent with the idea that the contraction of follicular SMC is necessary for hamster ovulation, and suggest that either stretch or neurotransmitters may initiate SMC contraction in vivo.

Animals↗
PubMed1999

Expression of the heterogenous nuclear ribonucleoprotein complex K protein and the prolyl-4-hydroxylase alpha-subunit in atherosclerotic arterial smooth muscle cells.

Smooth muscle cells (SMC) play a major role in the formation of atherosclerotic lesions found on major blood vessels. SMC proliferation, migration, and protein synthesis promote the progression of the early lesion, the fatty streak, into a complex myointimal fibrous plaque. To investigate altered gene expression in SMC during atherogenesis, we characterized differences between SMC from normal rabbits, rabbits fed a 2% cholesterol diet, and Watanabe Heritable Hyperlipidemic rabbits (WHHL). We detected and isolated a 501 bp cDNA fragment representing the A isoform of heterogenous nuclear ribonucleoprotein complex K (hnRNP-K) and a 281 bp cDNA fragment representing the prolyl-4-hydroxylase alpha-subunit (alphaPH) mRNAs. hn-RNP-K was upregulated in SMC from cholesterol-fed rabbits isolated in primary culture, as well as in SMC medial tissue from both the cholesterol-fed and WHHL rabbits. alphaPH was upregulated in SMC from the cholesterol-fed rabbits isolated in primary culture and in the tissue from WHHL rabbits. These data demonstrate genes consistent with increased proliferation and collagen production are upregulated in SMC during atherogenesis and may shed new light on gene expression changes and corresponding phenotype changes in SMC during atherogenesis.

Animals↗
PubMed1999

The kinase inhibitor fasudil (HA-1077) reduces intimal hyperplasia through inhibiting migration and enhancing cell loss of vascular smooth muscle cells.

Smooth muscle cell (SMC) migration plays an important role in restenosis after angioplasty. Myosin phosphorylation is necessary for cell migration. Fasudil is an inhibitor of protein kinases, including myosin light chain kinase and Rho associated kinase, thereby inhibiting myosin phosphorylation, and it has been clinically used to prevent vasospasm following subarachnoid hemorrage. Based on these findings, we examined the anti-migrative action of fasudil. In SMC (SM-3), fasudil (1-100 microM) inhibited SMC migration in a dose-dependent manner (p < 0.001). Fasudil suppressed actin stress fiber formation dose dependently. In rabbit carotid artery, fasudil (10 mg/kg/day) markedly reduced intimal hyperplasia 14 days following balloon injury. Cell kinetic study showed that fasudil did not affect proliferation but enhanced cell loss in the media after injury. We concluded that fasudil reduced neointimal formation after balloon injury through both inhibiting migration and enhancing cell loss of medial SMC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Cyclic AMP, early response gene expression, and DNA synthesis in rat smooth muscle cells.

Smooth muscle cells (SMC) isolated from neonatal and adult rats differ markedly in their growth characteristics. The growth of neonatal cells is mainly due to autocrine stimulation, whereas the growth of adult SMC is dependent upon addition of exogenous mitogens. Increasing intracellular cyclic AMP (cAMP) levels effectively inhibits DNA synthesis in adult cells, but is essentially without effect on the rate of DNA synthesis in neonatal cells. In the present study we investigated whether this difference in cAMP sensitivity is due to an effect of cAMP on early response genes. The results show that increasing intracellular levels of cAMP by exposing the cells to the synthetic adenosine analogue N-ethyl-carboxamido adenosine (NECA) results in an accumulation of c-jun and c-fos mRNA in both cell types. NECA also lowered c-myc mRNA levels in neonatal cells, whereas it marginally increased the presence of c-myc mRNA in adult cells. Exposure to NECA also resulted in a limited increase in alpha-actin mRNA levels. NECA did not inhibit DNA synthesis or growth of adult SMC actively proliferating in the presence of 10% serum, suggesting that cAMP interferes with processes taking place during the early G1 phase or in the entry of growth-arrested cells into the G1 phase of the SMC cell cycle. It is concluded that the growth-inhibitory effect of NECA is unlikely to be due to actions of cAMP on early response genes. However, it cannot be completely excluded that an increased synthesis of jun/fos transcription factors may induce the transcription of other, growth-suppressing genes in the cells.

Adenosine↗