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PubMed2006

A comparison of engineered urinary bladder and intestinal smooth muscle for urinary bladder wall replacement in a rabbit model.

BACKGROUND/PURPOSE: The small intestine is the most common resource for bladder augmentation. Little is known whether intestinal smooth muscle cells (SMCs) may be engineered into bladder tissue. We investigated the phenotypic and functional characteristics of engineered bladder and intestinal SMCs as bladder wall replacement in a rabbit model. METHODS: One month after an initial 70% partial cystectomy, 3 autoaugmentation surgeries were performed, including traditional autoaugmentation (TA, n = 6), TA using engineered bladder SMCs (TA + B, n = 6), and TA using intestinal SMCs (TA + I, n = 6). All were followed up by bladder volume measurement and retrieved on the first, third, and sixth month. The grafts and the native bladder wall were evaluated with immunocytochemistry and electrical field stimulation (EFS). Statistical analysis was performed using analysis of variance. RESULTS: Both the TA + I and TA + B groups showed significant and similar bladder capacity increment in all time points. The engineered muscle cells demonstrated the typical "contraction-relaxation" response to supramaximal EFS. There were no statistical differences in both the TA + I and TA + B groups in contractility force. CONCLUSION: Engineered SMCs derived from urinary bladder and small intestine could retain their phenotype after implantation in vivo. Both exhibited a similar degree of contractility to EFS. These results suggest that there are no phenotypic or functional differences between muscle cells obtained from the 2 different organs. Both have the potential to be engineered into normal bladder tissues.

Animals↗
PubMed2004

Aging and gastrointestinal smooth muscle.

The present review is an attempt to put into perspective the available information on the putative changes in cellular mechanisms of the contractile properties of the aging gastrointestinal (GI) smooth muscle. Information on smooth muscle of the GI tract is scanty. Smooth muscle cells from old rats (32 months old) exhibit limited cell length distribution and diminished contractility. The observed reduced contractile response may be due to the effect of aging on signal transduction pathways, especially an inhibition of the tyrosine kinase-Src kinase pathway, a reduced activation of the PKCalpha pathway, a reduced association of contractile proteins (HSP27-tropomyosin, HSP27-actin, and actin-myosin). Levels of HSP27-phosphorylation are also reduced compared to adult rats. Regulation of GI motility is a complex mechanism of signal transduction and interaction of signaling and contractile proteins. It is suggested that further studies to elucidate the role of HSP27 in aging smooth muscle of the GI tract are needed.

Aging↗
PubMed2005

Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2.

Hepatic stellate cells (HSC) cultured on plastic spontaneously transdifferentiate to a myofibroblast-like cell type (MFB). This model system of hepatic fibrogenesis is characterized by phenotypic changes of the cells and increased matrix synthesis. Here, we analyzed if transdifferentiation-dependent induction of ECM components, e.g., collagen type I and thrombospondin-2 (TSP-2), and phenotypic changes are coregulated events and if both processes are mediated via TGF-beta pathway(s). Blocking the TGF-beta-dependent p38 MAPK pathway in HSC with the specific inhibitor SB203580 strongly reduces collagen I and TSP-2 mRNA expression without inhibiting upregulation of the typical MFB-marker, alpha-smooth-muscle actin (alpha-SMA). Similarly, interference with the Smad2/3/4 pathway using dexamethasone also heavily decreased expression of collagen type I and TSP-2 whereas transdifferentiation of HSC to the typical morphology of MFB with loss of fat droplets and increasing alpha-SMA was unchanged. Further, p38 MAPK mediated induction of collagen I and TSP-2 expression by TGF-beta1 was still achieved in the presence of dexamethasone, showing that dexamethasone does not block p38 while it delays Smad2 phosphorylation and antagonizes stimulation of a Smad3/Smad4 dependent TGF-beta reporter construct. Interestingly, in contrast to SB203580 and dexamethasone, overexpression of the TGF-beta antagonist Smad7 reduced ECM expression and simultaneously inhibited morphologic transdifferentiation, indicating that Smad7 fulfills additional features in HSC. In conclusion, our data show that phenotypic changes of transdifferentiating HSC and induction of matrix synthesis are independent processes, the latter being stimulated by both, Smad dependent and MAPK dependent TGF-beta signaling.

Actins↗
PubMed2004

Direct chemotactic action of angiopoietin-1 on mesenchymal cells in the presence of VEGF.

Angiopoietin-1 (Ang1) and its receptor, Tie2, play an important role in angiogenesis and vessel maturation. We previously reported that overexpression of Ang1 in MCF7 xenograft tumors facilitated vessel stabilization by mural cells, and that cultured SMC express Tie2. Here, we investigated whether Ang1 directly acts as a chemoattractant on mural cells or their precursors. In a Matrigel plug assay, neither Ang1 nor VEGF alone induced angiogenesis but together stimulated infiltration of non-endothelial cells that were CD31-negative, vimentin-positive and also positive for VEGFR-1 and Tie2. While negative for smooth muscle actin, reactivity for desmin suggests that the cells are mural cell precursors. VEGF treatment of cultured smooth muscle cells (SMC) upregulated Tie2 and allowed for Ang1-mediated phosphorylation of Tie2 and the AKT serine-threonine kinase. The combination of Ang1 and VEGF stimulated SMC migration in a Boyden chamber-type assay. In the presence of VEGF, Tie2 is upregulated on mural cells, allowing for a migratory response to Ang1. These findings support the view that Ang1, in concert with VEGF, can act directly on mural cells or their precursors to facilitate their recruitment to new blood vessels. This action may play an important role in vascular stabilization.

Actins↗
PubMedDate not supplied

Modelling gastrointestinal bioelectric activity.

The development of an anatomically realistic biophysically based model of the human gastrointestinal (GI) tract is presented. A major objective of this work is to develop a modelling framework that can be used to integrate the physiological, anatomical and medical knowledge of the GI system. The anatomical model was developed by fitting derivative continuous meshes to digitised data taken from images of the visible man. Structural information, including fibre distributions of the smooth muscle layers and the arrangement of the networks of interstitial cells of Cajal, were incorporated using published information. A continuum modelling framework was used to simulate electrical activity from the single cell to the whole organ and body. Also computed was the external magnetic field generated from the GI electrical activity. The set of governing equations were solved using a combination of numerical techniques. Activity at the (continuum) cell level was solved using a high-resolution trilinear finite element procedure that had been defined from the previously fitted C1 continuous anatomical mesh. Multiple dipolar sources were created from the excitation waves which were embedded within a coupled C1 continuous torso model to produce both the cutaneous electrical field and the external magnetic field. Initial simulations were performed using a simplified geometry to test the implementation of the numerical solution procedure. The numerical procedures were shown to rapidly converge with mesh refinement. In the process of this testing, errors in a long standing analytic solution were identified and are corrected in Appendix B. Results of single cell activity were compared to published results illustrating that the key features of the slow wave activity were successfully replicated. Simulations using a two-dimensional slice through the gastric wall produced slow wave activity that agreed with the known frequency and propagation characteristics. Three-dimensional simulations were also performed using the full stomach mesh and results illustrated the slow wave propagation throughout the stomach musculature.

Animals↗
PubMed2004

Control of bladder function by peripheral nerves: avenues for novel drug targets.

The micturition reflex involves afferent nerve activation when the bladder is sufficiently full and subsequent controlled firing of parasympathetic efferent nerves to contract the detrusor muscle as part of the voiding mechanism. Alteration of the sensitivity of afferent activation or loss of control over transmitter release could lead to sensory- or motor-activated incontinence, respectively. The control mechanisms that regulate these 2 activities remain poorly understood. Current opinion is that the sensation of bladder fullness is relayed by afferent nerves in the mucosal layer, which are activated by the release of chemical mediators, such as adenosine triphosphate (ATP), from the urothelium when it is stretched as the bladder fills. This hypothesis supports the concept that other chemical signals that affect bladder sensation (eg, changes in urine composition and agents such as capsaicin) can modulate the sensitivity of the basic system. It has also been proposed that a layer of myofibroblasts immediately below the basal lamina of the urothelium acts as a variable gain regulator of the sensory process between ATP release and afferent excitation. These myofibroblasts are functionally connected to form an electrical syncytium, make close contact with nerves, and respond by generating electrical responses and transient increases in intracellular Ca2+ when exposed to ATP. On the efferent side, using a guinea pig detrusor model, possible modulators of transmitter release have been investigated, including adenosine (the breakdown product of the neurotransmitter ATP). Adenosine reduces the force of nerve-mediated contractions by acting predominantly at presynaptic sites at the nerve-muscle junction via a subtype of an adenosine receptor-the A1 receptor. An additional effect, possibly via A2 receptors, is also present on the detrusor muscle itself. These actions of adenosine are less evident in human detrusor muscle but remain a potential modulatory target. In summary, the cellular and molecular regulation of bladder fullness sensation and efferent transmitter release are becoming better understood and represent potential drug targets for the management of detrusor overactivity.

Adenosine↗
PubMed2004

Routine bladder biopsies in men with bladder outlet obstruction?

OBJECTIVES: To establish whether routine evaluation of light microscopic changes in bladder biopsies in men with graded bladder outlet obstruction correlates with urodynamic parameters and to evaluate the performance of two pathologists in bladder biopsy interpretation. METHODS: In 63 consecutive patients presenting with lower urinary tract symptoms suggestive of bladder outlet obstruction, the workup included bladder biopsies, which were semiquantitatively and independently evaluated by two pathologists for fibrosis, elastosis, muscle cell degeneration, inflammation, and additional remarkable findings. Furthermore, as determined by their general impression, the pathologists gave a diagnosis of normal or graded abnormality. The pathologists' performance was compared and the clinical and urodynamic data were correlated to the consensus histologic diagnoses. RESULTS: Fifty-four of 63 cases could be evaluated. The intraobserver and interobserver reproducibility were reasonable, with a kappa of 0.35 and 0.50, respectively. The consensus diagnosis of abnormal bladder biopsy correlated with impaired bladder compliance and capacity. However, no correlation was found between the presence and severity of histologic abnormalities and Schäfer class, urethral resistance factor, instability, postvoid residual urine volume, symptom score, and prostate volume. CONCLUSIONS: Although abnormal bladder biopsies correlated significantly with impaired bladder capacity and compliance, routine evaluation of bladder biopsies is not indicated in the evaluation of bladder outlet obstruction.

Biopsy↗
PubMed2004

Spontaneous activity and electrical coupling in human detrusor smooth muscle: implications for detrusor overactivity?

Large uncontrollable detrusor contractions, decreased compliance that increases luminal pressures during filling, and detrusor underactivity are all examples of abnormal bladder function. Studies of the nervous control of lower urinary tract function and measurement of the cellular properties of the component tissues of the bladder wall have been performed to deepen our knowledge of these problems. The resultant data have suggested that lower urinary tract smooth muscle should not be regarded solely as a collection of independent cellular contractile units that are each activated by separate neural inputs, but also as a syncytium of cells. Although this syncytial arrangement may not be as well developed as in other tissues, it should impose a new layer of activity that will affect overall bladder function. Recent studies have addressed this issue through investigation of spontaneous contractile activity, the cellular basis of syncytial function, and their normal and abnormal functional consequences. The results suggest that individual detrusor cells possess membrane properties that may lead to spontaneous activity fluctuations, which can affect adjacent cells and, thus, produce multicellular aberrant responses. It remains unclear whether these responses manifest themselves as dysfunctional activity in the whole bladder defects because the extent of local multicellular abnormalities is not known at present. The data do imply that myogenic defects can contribute to abnormal bladder function and, thus, suggest several new targeted drug models that should be explored.

Animals↗
PubMed2004

Response of bladder smooth muscle cells to obstruction: signal transduction and the role of mechanosensors.

Bladder hypertrophy and detrusor overactivity are well-known bladder responses to outlet obstruction. Mechanical stretch stress is considered the trigger inducing these responses in the urodynamically overloaded bladder. Several studies using an in vitro model of mechanical stress demonstrate that repetitive stretch stimulation of bladder smooth muscle cells results in increased expression of a variety of growth factors and other specific proteins. In the bladder smooth muscle cell, stretch-activated ion channels (SACs) and protein kinase C (PKC) sarcolemmal proteins may function as sensors for external mechanical forces. In particular, SACs couple mechanical stress to activation of c-jun NH2-terminal kinase, which leads to a rapid induction of nuclear transcription factors. PKC also may involve an indirect or direct regulation of nuclear events. In addition, mechanical stress may induce the release of angiotensin II in an autocrine fashion. These factors in turn stimulate expression of specific gene-encoding proteins, such as heparin-binding epidermal growth factor-like growth factor, nerve growth factor, and an isomer of cyclooxygenase-2, all of which have the potential to contribute to structural and functional alterations in the bladder after obstruction.

Animals↗
PubMed2004

Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin.

Injury of the tubular epithelium and TGF-beta1-induced conversion of epithelial cells to alpha-smooth muscle actin (SMA)-expressing myofibroblasts are key features of kidney fibrosis. Since injury damages intercellular junctions and promotes fibrosis, we hypothesized that cell contacts are critical regulators of TGF-beta 1-triggered epithelial-to-mesenchymal transition (EMT). Here we show that TGF-beta 1 was unable to induce EMT in intact confluent monolayers, but three different models of injury-induced loss of epithelial integrity (subconfluence, wounding, and contact disassembly by Ca(2+)-removal) restored its EMT-inducing effect. This manifested in loss of E-cadherin, increased fibronectin production and SMA expression. TGF-beta 1 or contact disassembly alone only modestly stimulated the SMA promoter in confluent layers, but together exhibited strong synergy. Since beta-catenin is a component of intact adherens junctions, but when liberated from destabilized contacts may act as a transcriptional co-activator, we investigated its role in TGF-beta 1-provoked EMT. Contact disassembly alone induced degradation of E-cadherin and beta-catenin, but TGF-beta1 selectively rescued beta-catenin and stimulated the beta-catenin-driven reporter TopFLASH. Moreover, chelation of free beta-catenin with the N-cadherin cytoplasmic tail suppressed the TGF-beta1 plus contact disassembly-induced SMA promoter activation and protein expression. These results suggest a beta-catenin-dependent two-hit mechanism in which both an initial epithelial injury and TGF-beta 1 are required for EMT.

Actins↗
PubMed2003

Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells.

Three HIF-alpha prolyl-4-hydroxylases (PHDs) (named PHD1, PHD2, and PHD3) effect the proteasome-mediated degradation of HIF by catalyzing the hydroxylation of key proline residues in the HIF-1 alpha subunit under normoxic conditions. When oxygen tension is reduced, PHD-mediated hydroxylation cannot occur, HIF-1 alpha accumulates in the nucleus, resulting in HIF-mediated gene transcription. In the present study, the expression and regulation of PHD mRNA and HIF protein expression was examined in human tissues and primary cells of cardiovascular origin. Treatment of human cardiac myocytes, smooth muscle cells, and endothelial cells with hypoxia or CoCl(2), a hypoxia mimic, resulted in a significant time-dependent increase in PHD3, but not PHD1 or PHD2, mRNA levels, which correlated with an increase in HIF-1 alpha protein expression. Overexpression studies revealed that PHD3 levels influence HIF-1 alpha stability in both normoxic and hypoxic conditions, suggesting that PHD3 may participate in a feedback loop controlling HIF activity.

Base Sequence↗
PubMed2003

The regulating effect of heme oxygenase/carbon monoxide on hypoxic pulmonary vascular structural remodeling.

Hypoxic pulmonary vascular structural remodeling (HPVSR) is the important pathologic basis of hypoxic pulmonary hypertension (HPH). The discoveries of endogenous gaseous messenger molecules, nitric oxide (NO) and carbon monoxide (CO), have been moving the research of HPVSR to a very new phase. But the effect and significance of heme oxygenase (HO)/CO on the development of HPVSR have not been fully understood. In this study, we observed the alteration of endogenous HO/CO system in five time points during 14 days and found that the content of CO in lung homogenates in rats with HPVSR increased in a time-dependent double-peak manner. Exogenous supply of ZnPP-IX, an inhibitor of HO-1, decreased the content of CO in lung homogenate, decreased the expression of Fas and apoptotic cells in pulmonary artery smooth muscle cells (PASMCs), up-regulated the expression of PCNA in PASMCs, and worsened HPH and HPVSR of hypoxic rats. Meanwhile, exogenous supply of CO played an adverse action. The results showed that the up-regulation of HO/CO exerted a protective role in the development of HPVSR.

Animals↗
PubMed2006

Cysteinyl leukotriene D4 increases human detrusor muscle responsiveness to histamine.

PURPOSE: Leukotriene D(4) and histamine are proinflammatory mediators that are released concomitantly by activated mast cells. There is the possibility of mutual potentiation of their actions in inflammatory diseases such as interstitial cystitis. We investigated whether human detrusor smooth muscle cells showed increased responsiveness to histamine in the presence of leukotriene D(4). MATERIALS AND METHODS: Cold cup detrusor biopsies were obtained from patients undergoing cystoscopy for benign noninvasive bladder diseases. Human detrusor smooth muscle cells in culture were obtained using an explantation technique and subcultivated for a maximum of 3 passages. The cytosolic free Ca(2+) concentration and contractile force were measured by spectrofluorometry and myograph techniques, respectively. RESULTS: Low doses of leukotriene D(4) (10 nM or less), which usually do not produce a significant effect on the free Ca(2+) concentration or on muscle contraction when administered 30 to 60 seconds beforehand, significantly enhanced the transient increase in the free Ca(2+) concentration and isometric force induced by 50 to 200 nM histamine. Increased histamine responses were associated with an upward shift in the fura-2 fluorescence ratio, suggesting that histamine hyperresponsiveness was due to the appearance of additional histamine receptors on the sarcolemma or to more efficient signaling per receptor. Leukotriene D(4) concentrations greater than 10 nM had no potentiating effects. CONCLUSIONS: To our knowledge this is the first demonstration in the human detrusor that leukotriene D(4) potentiates the effect of histamine. These inflammatory mediators, which are often released concomitantly from mast cells, may interact mutually to potentiate the spasmogenic effect of histamine. These results suggest that the combination of leukotriene D(4) and histamine H1 receptor antagonists may be more effective for the treatment of interstitial cystitis than when given alone.

Calcium↗
PubMed2003

Ultrastructure of airway smooth muscle.

There is an abundance of ultrastructural data in the literature on vascular, visceral, and other smooth muscles; such data on airway smooth muscle, however, are conspicuously missing. Here we present a series of electron micrographs depicting contractile and cytoskeletal elements as well as organelles in porcine trachealis. Myosin thick filaments are present in the relaxed muscle; thick filament density increases substantially when the muscle is activated. Actin thin filaments are present in large excess over the thick filaments; the thin/thick filament ratio is about 31/1 in the relaxed state; this ratio is reduced to about 22/1 when the muscle is activated. The sarcoplasmic reticulum is often found associated with caveolae and mitochondria. Cells within a bundle are well connected by intermediate and gap junctions. The results demonstrate that quantitative morphological analysis of ultrastructure of airway smooth muscle fixed under different functional states is possible and will be essential in elucidating the structural basis of adaptation and contraction of the muscle.

Actins↗
PubMed2003

Airway smooth muscle growth from the perspective of animal models.

Airway smooth muscle maintains airway tone and may assist in adjusting ventilation distribution within the normal lung. Alterations in the properties or the quantity of ASM are likely responsible for some instances of airways hyperresponsiveness to bronchoconstrictive stimuli that is a characteristic of diseases such as asthma. Morphometric studies have shown an increase in the mass of ASM in human asthmatic airways. Animal models have been developed that confirm that ASM can be induced to grow by allergic sensitization and challenge. Growth is in large part by hyperplasia as measured by incorporation of bromodeoxyuridine as a marker of the S-phase of the cell cycle. T cells, in particular CD4+ cells, may participate in the stimulation of growth of ASM by allergen challenge. The growth factors responsible for the increase in ASM are as yet unidentified but two mediators associated with allergic airway responses, cysteinyl leukotrienes and endothelin, have been implicated using specific receptor antagonists. The links between T cells and the biochemical mediators of growth have not been established.

Adaptation, Physiological↗
PubMed2003

Airway smooth muscle: immunomodulatory cells that modulate airway remodeling?

Although the pathogenesis of asthma remains unclear, substantial progress has been made over the past decades in the characterization of airway inflammation as a pathogenetic mechanism in asthma. New evidence suggests that airway smooth muscle (ASM), the most important cell modulating bronchomotor tone, plays an important immunomodulatory role in the orchestration and perpetuation of airway inflammation. Evidence now suggests that the signaling pathways that modulate leukocyte function may be disparate from those found in resident effector cells such as ASM, fibroblasts and epithelial cells. Further investigation and understanding of the critical signaling pathways that modulate ASM cell release, secretion of chemokines/cytokines and expression of cell adhesion molecules (CAMs) may offer new therapeutic approaches in the treatment of asthma.

Adaptation, Physiological↗
PubMed2002

Smooth muscle myosin filament assembly under control of a kinase-related protein (KRP) and caldesmon.

Kinase-related protein (KRP) and caldesmon are abundant myosin-binding proteins of smooth muscle. KRP induces the assembly of unphosphorylated smooth muscle myosin filaments in the presence of ATP by promoting the unfolded state of myosin. Based upon electron microscopy data, it was suggested that caldesmon also possessed a KRP-like activity (Katayama et al., 1995, J Biol Chem 270: 3919-3925). However, the nature of its activity remains obscure since caldesmon does not affect the equilibrium between the folded and unfolded state of myosin. Therefore, to gain some insight into this problem we compared the effects of KRP and caldesmon, separately, and together on myosin filaments using turbidity measurements, protein sedimentation and electron microscopy. Turbidity assays demonstrated that KRP reduced myosin filament aggregation, while caldesmon had no effect. Additionally, neither caldesmon nor its N-terminal myosin binding domain (N152) induced myosin polymerization at subthreshold Mg2+ concentrations in the presence of ATP, whereas the filament promoting action of KRP was enhanced by Mg2+. Moreover, the amino-terminal myosin binding fragment of caldesmon, like the whole protein, antagonizes Mg(2+)-induced myosin filament formation. In electron microscopy experiments, caldesmon shortened myosin filaments in the presence of Mg2+ and KRP, but N152 failed to change their appearance from control. Therefore, the primary distinction between caldesmon and KRP appears to be that caldesmon interacts with myosin to limit filament extension, while KRP induces filament propagation into defined polymers. Transfection of tagged-KRP into fibroblasts and overlay of fibroblast cytoskeletons with Cy3KRP demonstrated that KRP colocalizes with myosin structures in vivo. We propose a new model that through their independent binding to myosin and differential effects on myosin dynamics, caldesmon and KRP can, in concert, control the length and polymerization state of myosin filaments.

Adenosine Triphosphate↗