Vascular Smooth Muscle Cells (vascular + smooth_muscle_cell)

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Distribution within Medical Sciences

Terms modified by Vascular Smooth Muscle Cells

  • vascular smooth muscle cell proliferation

  • Selected Abstracts


    PARATHYROID HORMONE HAS A PROSCLEROTIC EFFECT ON VASCULAR SMOOTH MUSCLE CELLS

    NEPHROLOGY, Issue 1 2002
    Vlado Perkovic
    [source]


    PIOGLITAZONE INHIBITS HOMOCYSTEINE-INDUCED MIGRATION OF VASCULAR SMOOTH MUSCLE CELLS THROUGH A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ,-INDEPENDENT MECHANISM

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2008
    Li Li
    SUMMARY 1Peroxisome proliferator-activated receptor (PPAR)-, agonists have been demonstrated to exert protective effects against homocysteine (Hcy)-induced pathogenesis. However, the effects of PPAR-, agonists on Hcy-induced migration are unknown. In the present study, we examined the effect of pioglitazone on the migration of vascular smooth muscle cells (VSMC) induced by Hcy and the possible mechanism involved. 2Vascular smooth muscle cells were isolated from the thoracic aortas of male Sprague-Dawley rats. The migration of VSMC was examined using a transwell technique. The generation of intracellular reactive oxygen species (ROS) was measured using the ROS-sensitive fluoroprobe 2,,7,-dichlorodihydrofluorescein diacetate. The activity of NAD(P)H oxidase was assessed by lucigenin enhanced chemiluminescence. Activation of p38 mitogen-activated protein kinase (MAPK) was determined by western blotting. 3The results showed that pioglitazone dose-dependently inhibited the migration of VSMC induced by Hcy. This was not reversed by the PPAR-, antagonist GW9662. In addition, pretreatment with the NAD(P)H oxidase inhibitor diphenylene iodonium (DPI), the free radical scavenger N -acetylcysteine and the p38 MAPK inhibitor SB202190 blocked Hcy-induced VSMC migration. Furthermore, we observed that pioglitazone suppressed Hcy-induced intracellular ROS production; similar effects were observed with DPI and NAC. Pioglitazone attenuated Hcy-induced activation of NAD(P)H oxidase. Moreover, pioglitazone blocked Hcy-induced p38 MAPK phosphorylation; similar effects were observed for DPI, NAC and SB202190. 4The data demonstrate that pioglitazone inhibits Hcy-induced VSMC migration that is independent of PPAR-,. Furthermore, part of the biological effect of pioglitazone involves a decrease in the levels of NAD(P)H oxidase derived-ROS and p38 MAPK activation. [source]


    STIMULATION OF OESTROGEN RECEPTOR-EXPRESSING ENDOTHELIAL CELLS WITH OESTROGEN REDUCES PROLIFERATION OF COCULTURED VASCULAR SMOOTH MUSCLE CELLS

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2008
    Malin Odenlund
    SUMMARY 1Oestrogen reduces vascular smooth muscle cell proliferation in mouse vascular injury models. Data on the antiproliferative effect of oestrogen in cultured vascular smooth muscle cells (VSMC) are less conclusive than those obtained in whole animal studies. 2In the present study, we investigated the hypothesis that oestrogen-induced attenuation of VSMC proliferation is facilitated by the presence of endothelial cells (EC) using a coculture system of EC and VSMC. 3Treatment with a physiological concentration of oestrogen (17,-estradiol (E2); 100 nmol/L) had no effect on fetal calf serum (FCS)-stimulated DNA synthesis in either A7r5 VSMC or bEnd.3 EC. However, stimulation of bEnd. 3 cells with E2 in a coculture system of bEnd.3 and A7r5 cells reduced FCS-induced DNA synthesis in A7r5 cells by approximately 45%. The nitric oxide synthase inhibitor NG -nitro- l- arginine methyl ester (l -NAME; 100 µmol/L) did not reverse the oestrogen-induced attenuation of DNA synthesis. The antiproliferative effect of E2 may be mediated via either oestrogen receptor (ER) ,, ER, or both because the bEnd.3 cells expressed immunoreactivity for both ER subtypes. 4These data show that ER,- and ER,-expressing endothelial cells, which are stimulated with a physiological concentration of oestrogen, release a factor(s) that arrests the proliferation of cocultured VSMC. Oestrogen-induced attenuation of vascular smooth muscle cell proliferation is not prevented by l -NAME, suggesting that a mechanism other than endothelial NO is involved. [source]


    Aging Increases the Interleukin-1,,Induced INOS Gene Expression and Nitric Oxide (NO) Production in Vascular Smooth Muscle Cells

    JOURNAL OF CARDIAC SURGERY, Issue 6 2002
    Gabriel HH Chan
    Objectives: Inducible form of nitric oxide synthase (iNOS) is induced by cytokines (e.g. interleukin-1, (IL-1,)) during pathological conditions, such as sepsis. Excessive NO synthesis in blood vessels during sepsis can result in massive vasodilation and life-threatening hypotension. In addition, chronic expression of iNOS contributes to onset of diabetes, autoimmune diseases, arthritis, renal toxicity, and neurodegenerative disorders. The purpose of the present study was to examine the effect of aging on the levels of expression of iNOS induced by a low concentration (5 ng/ml) of IL-1, in VSMCs. Methods: Gene expression of iNOS was determined by RT-PCR and analysis of the PCR products by both agarose gel electrophoresis and capillary electrophoresis with laser-induced fluorescence detector (CE-LIF). This new CE-LIF technique, just developed in our laboratory, provides greater than 1,000 fold better sensitivity compared to agarose gels. The production of nitrite, the stable metabolite of NO, was measured (by a modified Griess reaction) in the media of cultured VSMCs isolated from young and elderly rats (3-month and 20-months old, respectively) of both genders following the exposure to IL-1, (5 ng/ml). VSMCs were used in their 1st passage to avoid phenotypic changes that typically occur in cultures of VSMCs after 3-10 passages. Results: IL-1, (5 ng/ml) caused a much larger increase in iNOS mRNA in VSMCs of elderly rats as compared to young rats. Furthermore, IL-1, (5 ng/ml) had no significant effect on nitrite levels in VSMCs of young, but significantly increased nitrite levels by 7.9 fold in VSMCs from elderly male rats and by 2.6 fold in VSMCs from elderly female rats, as compared to young rats. A report had previously shown that the neuropeptide CGRP could synergistically enhance the expression of iNOS caused by IL-1, in later passages (10-15 passages) of rat aortic VSMCs (i.e. phenotypically modulated VSMCs). We found that IL-1, and CGRP together did not act synergistically to increase production of nitrite in our phenotypically normal (1st passage) VSMCs. Conclusion: IL-1,, at a low concentration (5 ng/ml), preferentially induces iNOS expression and increases production of NO in VSMCs of elderly rats as compared to young rats. The data suggest that aging enhances the responsiveness of VSMCs to the iNOS-inducing actions of the cytokine IL-1,. This may be a contributing factor in the increased risk of developing severe hypotension in elderly patients with sepsis. (Supported by a Direct Grant for Research). [source]


    ATP-Sensitive K+ Channels of Vascular Smooth Muscle Cells

    JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2003
    WILLIAM C. COLE Ph.D.
    ATP-sensitive potassium channels (KATP) of vascular smooth muscle cells represent potential therapeutic targets for control of abnormal vascular contractility. The biophysical properties, regulation and pharmacology of these channels have received intense scrutiny during the past twenty years, however, the molecular basis of vascular KATP channels remains ill-defined. This review summarizes the recent advancements made in our understanding of the molecular composition of vascular KATP channels with a focus on the evidence that hetero-octameric complexes of Kir6.1 and SUR2B subunits constitute the vascular KATP subtype responsible for control of arterial diameter by vasoactive agonists. [source]


    (-)-Epigallocatechin Gallate Inhibits Endothelin-1-Induced C-Reactive Protein Production in Vascular Smooth Muscle Cells

    BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2010
    Chen-Jing Wang
    Based on our previous study, the effect of EGCG on endothelin-1 (ET-1)-induced CRP production in rat vascular smooth muscle cells (VSMCs) and the possible mechanism were observed. The in vitro experiments showed that EGCG concentration-dependently inhibited ET-1-stimulated expression of CRP both in protein and mRNA levels in VSMCs as determined by the immunocytochemical staining, the enzyme-linked immunosorbent assay and the real-time quantitative polymerase chain reaction (RT-qPCR). The in vivo investigation with the double-labelled immunofluorescence staining and RT-qPCR displayed that EGCG also prevented ET-1-induced CRP expression in protein and mRNA levels in the aortic VSMCs of rats receiving the subchronic infusion of ET-1. In addition, EGCG suppressed reactive oxygen species (ROS) generation evoked by ET-1 in VSMCs as observed by the fluorescence probe. These demonstrate that EGCG may inhibit ET-1-stimulated generation of CRP in VSMCs so to relieve the inflammatory response and oxidative stress via blocking ROS signal, which provides new evidence for an anti-atherosclerotic effect of EGCG. [source]


    Altered Mitogen-Activated Protein Kinase Activation In Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2002
    Takao Kubo
    SUMMARY 1.,We previously reported that activation function of mitogen-activated protein kinases (MAPK) is enhanced in aorta strips from both prehypertensive and hypertensive spontaneously hypertensive rats (SHR) and that this enhancement of MAPK activation results from enhanced MAPK activation reactivity to angiotensin (Ang) II in SHR aorta strips. 2.,The purpose of the present study was to examine whether the enhanced function of the vascular angiotensin system observed in SHR aorta strips results from genetic alterations of vascular smooth muscle cells from SHR. 3.,Basal MAPK activity was within normal limits in cells from 4-week-old SHR, whereas enzyme activity was enhanced in 9-week-old SHR compared with age-matched Wistar-Kyoto (WKY) rats. 4.,Mitogen-activated protein kinase activation reactivity to AngII and endothelin-1 was enhanced in 9-week-old SHR cells but not in 4-week-old SHR cells. The enhancement of basal MAPK activity in 9-week-old SHR cells was abolished by a combination of the angiotensin AT1 receptor antagonist losartan and the endothelin receptor antagonist BQ123. 5.,These findings suggest that MAPK activation function in 4-week-old SHR cells is not enhanced. Thus, it appears that factors outside vascular smooth muscle cells are needed for the enhanced MAPK activation observed in 4-week-old SHR aorta strips. In 9-week-old SHR, MAPK activation function is enhanced in cells themselves and this function may, at least in part, contribute to the enhanced MAPK activation observed in SHR aorta strips. [source]


    Platelet-derived growth factor receptors expressed in response to injury of differentiated vascular smooth muscle in vitro: effects on Ca2+ and growth signals

    ACTA PHYSIOLOGICA, Issue 2 2001
    A. Lindqvist
    Vascular smooth muscle cells (VSMCs) in the intact vascular wall are differentiated for contraction, whereas the response to vascular injury involves transition towards a synthetic phenotype, with increased tendency for proliferation. Platelet-derived growth factor (PDGF) is thought to be important for this process. We investigated expression and functional coupling of PDGF receptors (PDGFRs) , and , in rat tail arterial rings kept in organ culture, in order to capture early events in the phenotypic transition. In freshly dissected rings no PDGFR immunoreactivity was found in medial VSMCs, whereas PDGFR , was detected in nerve fibres. After organ culture for 1,4 days PDGFR , and , as well as phospholipase C,2 (PLC,2), known to couple to PDGFR, were expressed in VSMCs within 100 ,m of the cut ends. Calponin, a marker for the contractile phenotype, was decreased near the injured area, suggesting that cells were in transition towards synthetic phenotype. In these cells, which showed functional Ca2+ -release from the sarcoplasmic reticulum, PDGF-AB (100 ng mL,1) had no effect on [Ca2+]i, whereas cultured VSMCs obtained from explants of rat tail arterial rings responded to PDGF-AB with an increase in [Ca2+]i. However, PDGFR within the cultured rings coupled to growth signalling pathways, as PDGF-AB caused a tyrphostin AG1295-sensitive activation of extracellular signal-regulated kinases 1 and 2 and of [3H]-thymidine incorporation. Thus, early expression of PDGFR in VSMC adjacent to sites of vascular injury coincides with signs of dedifferentiation. These receptors couple to growth signalling, but do not activate intracellular Ca2+ release. [source]


    High-phosphate-induced calcification is related to SM22, promoter methylation in vascular smooth muscle cells

    JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2010
    Addy Montes de Oca
    Abstract Hyperphosphatemia is closely related to vascular calcification in patients with chronic kidney disease. Vascular smooth muscle cells (VSMCs) exposed to high phosphate concentrations in vitro undergo phenotypic transition to osteoblast-like cells. Mechanisms underlying this transdifferentiation are not clear. In this study we used two in vitro models, human aortic smooth muscle cells and rat aortic rings, to investigate the phenotypic transition of VSMCs induced by high phosphate. We found that high phosphate concentration (3.3,mmol/L) in the medium was associated with increased DNA methyltransferase activity and methylation of the promoter region of SM22,. This was accompanied by loss of the smooth muscle cell,specific protein SM22,, gain of the osteoblast transcription factor Cbfa1, and increased alkaline phosphatase activity with the subsequent in vitro calcification. The addition of a demethylating agent (procaine) to the high-phosphate medium reduced DNA methyltransferase activity and prevented methylation of the SM22, promoter, which was accompanied by an increase in SM22, expression and less calcification. Additionally, downregulation of SM22,, either by siRNA or by a methyl group donor (S -adenosyl methionine), resulted in overexpression of Cbfa1. In conclusion, we demonstrate that methylation of SM22, promoter is an important event in vascular smooth muscle cell calcification and that high phosphate induces this epigenetic modification. These findings uncover a new insight into mechanisms by which high phosphate concentration promotes vascular calcification. © 2010 American Society for Bone and Mineral Research [source]


    Differential Effects of Vitamin D Analogs on Vascular Calcification,,

    JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2007
    Anna Cardśs
    Abstract We tested the effects of calcitriol and its analog paricalcitol on VSMC calcification in vitro and in vivo. For that reason, cells and animals with five-sixths nephrectomy were treated with both compounds. Calcitriol, but not paricalcitol, increased VSMC calcification in vitro and in vivo independently of calcium and phosphate levels. This increase in calcification was parallel to an increase in the RANKL/OPG ratio. Introduction: Vascular calcification is a common finding in patients with endstage renal disease. Furthermore, those patients often present secondary hyperparathyroidism, partly because of a decrease of calcitriol synthesis on the kidney. Thus, one of the main therapeutic options is to treat those patients with calcitriol or analogs. However, this treatment presents unwanted side effects, such as increases in vascular calcification. Materials and Methods: We tested the effect on vascular smooth muscle cell (VSMC) calcification of calcitriol and one of its analogs, paricalcitol, in vitro and in vivo in animals with endstage renal disease. Results: Calcitriol increased calcification of VSMCs cultured in calcification media. This effect was not present when cells were incubated with paricalcitol. Furthermore, only cells incubated with calcitriol showed an increased RANKL/ osteoprotegerin (OPG) expression. Animals with renal failure treated with hypercalcemic doses of calcitriol and paricalcitol showed an increase in systolic blood pressure. However, diastolic blood pressure only raised significantly in those animals treated with paricalcitol. This effect led to a significant increase in pulse pressure in animals treated with calcitriol. The increase in pulse pressure was likely caused by the extensive calcification observed in arteries of animals treated with calcitriol. This increase in calcification was not seen in arteries of animals treated with paricalcitol, despite having similar levels of serum calcium and phosphorus as animals treated with calcitriol. Furthermore, the decreases in serum PTH levels were similar in both treatments. Conclusions: We conclude that paricalcitol has a different effect than calcitriol in VSMC calcification and that this could explain part of the differences observed in the clinical settings. [source]


    Close relation of arterial ICC-like cells to the contractile phenotype of vascular smooth muscle cell

    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2007
    Vladimķr Pucovskż
    Abstract This work aimed to establish the lineage of cells similar to the interstitial cells of Cajal (ICC), the arterial ICC-like (AIL) cells, which have recently been described in resistance arteries, and to study their location in the artery wall. Segments of guinea-pig mesenteric arteries and single AIL cells freshly isolated from them were used. Confocal imaging of immunostained cells or segments and electron microscopy of artery segments were used to test for the presence and cellular localization of selected markers, and to localize AIL cells in intact artery segments. AIL cells were negative for PGP9.5, a neural marker, and for von Willebrand factor (vWF), an endothelial cell marker. They were positive for smooth muscle ,-actin and smooth muscle myosin heavy chain (SM-MHC), but expressed only a small amount of smoothelin, a marker of contractile smooth muscle cells (SMC), and of myosin light chain kinase (MLCK), a critical enzyme in the regulation of smooth muscle contraction. Cell isolation in the presence of latrunculin B, an actin polymerization inhibitor, did not cause the disappearance of AIL cells from cell suspension. The fluorescence of basal lamina protein collagen IV was comparable between the AIL cells and the vascular SMCs and the fluorescence of laminin was higher in AIL cells compared to vascular SMCs. Moreover, cells with thin processes were found in the tunica media of small resistance arteries using transmis-sion electron microscopy. The results suggest that AIL cells are immature or phenotypically modulated vascular SMCs constitutively present in resistance arteries. [source]


    Modulation of cyclin dependent kinase inhibitor proteins and ERK1/2 activity in allylamine-injured vascular smooth muscle cells

    JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2004
    Sarah A. Jones
    Abstract Chronic oxidative injury by allylamine (AAM) induces proliferative vascular smooth muscle cell (vSMC) phenotypes in the rat aorta similar to those seen in rodent and human atherosclerotic lesions. The proliferative advantage of AAM vSMC compared to control cells is maintained with serial passage of the cells and the advantage is nullified when AAM cells are seeded on a collagen substrate. In this study, we evaluate the potential role of cyclin dependent kinase inhibitors, p27 and p21, and mitogen activated protein (MAP) kinases, ERK1/2, in mediating the proliferative advantage of AAM stressed vSMC over control cells on plastic or collagen substrates. p27 levels in randomly cycling cells were comparable in both cell types irrespective of the substrate. In contrast, basal levels of p21 were 1.9,±,0.3 (P,<,0.05)-fold higher in randomly cycling AAM cells seeded on plastic compared to controls, a difference that was lost on a collagen substrate. Following G0 synchronization, basal levels of both p27 and p21 were higher in AAM cells seeded on plastic compared to controls (1.7,±,0.2 and 2.0,±,0.3-fold, respectively, P,<,0.05), but these differences were lost upon mitogenic stimulation. Pyrrolidine dithiocarbamate (PDTC) decreased p27 and p21 levels in cycling AAM cells relative to controls in a substrate-dependent manner. AAM cells seeded on plastic exhibited enhanced ERK1/2 activation upon mitogenic stimulation; seeding on collagen nullified this advantage. The duration of ERK1/2 activation was prolonged in AAM cells independently of the seeding substrate. We conclude that substrate-dependent acquisition of proliferative phenotypes following repeated cycles of AAM injury correlates with modulation of the cyclin dependent kinase inhibitors, p27 and p21. © 2004 Wiley-Liss, Inc. [source]


    Age-related differences in insulin-like growth factor-1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cells

    JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2008
    Muyao Li
    Advanced age is a major risk factor for atherosclerosis, but how aging per se influences pathogenesis is not clear. Insulin-like growth factor-1 receptor (IGF-1R) promotes aortic vascular smooth muscle cell (VSMC) growth, migration, and extracellular matrix formation, but how IGF-1R signaling changes with age in VSMC is not known. We previously found age-related differences in the activation of Akt/FOXO3a and ERK1/2 pathways in VSMC, but the upstream signaling remains unclear. Using explanted VSMC from Fischer 344/Brown Norway F1 hybrid rats shown to display age-related vascular pathology similar to humans, we compared IGF-1R expression in early passages of VSMC and found a constitutive activation of IGF-1R in VSMC from old compared to young rats, including IGF-1R expression and its tyrosine kinase activity. The link between IGF-1R activation and the Akt/FOXO3a and ERK pathways was confirmed through the induction of IGF-1R with IGF-1 in young cells and attenuation of IGF-1R with an inhibitor in old cells. The effects of three kinase inhibitors: AG1024, LY294002, and TCN, were compared in VSMC from old rats to differentiate IGF-1R from other upstream signaling that could also regulate the Akt/FOXO and ERK pathways. Genes for p27kip-1, catalase and MnSOD, which play important roles in the control of cell cycle arrest and stress resistance, were found to be FOXO3a-targets based on FOXO3a-siRNA treatment. Furthermore, IGF-1R signaling modulated these genes through activation of the Akt/FOXO3a pathway. Therefore, activation of IGF-1R signaling influences VSMC function in old rats and may contribute to the increased risk for atherosclerosis. J. Cell. Physiol. 217: 377,387, 2008. © 2008 Wiley-Liss, Inc. [source]


    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit vascular smooth muscle cell proliferation via differential effects on the cell cycle

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2003
    Gavin Brooks
    ABSTRACT Abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of both atherosclerosis and restenosis. Recent studies suggest that high-dose salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in-vitro and in-vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAIDs) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains to be shown. In this study, we demonstrate that the NSAIDs aspirin, sodium salicylate, diclofenac, ibuprofen, indometacin and sulindac induce a dose-dependent inhibition of proliferation in rat A10 VSMCs in the absence of significant cytotoxicity. Flow cytometric analyses showed that exposure of A10 cells to diclofenac, indometacin, ibuprofen and sulindac, in the presence of the mitotic inhibitor, nocodazole, led to a significant G0/G1 arrest. In contrast, the salicylates failed to induce a significant G1 arrest since flow cytometry profiles were not significantly different from control cells. Cyclin A levels were elevated, and hyperphosphorylated p107 was present at significant levels, in salicylate-treated A10 cells, consistent with a post-G1/S block, whereas cyclin A levels were low, and hypophosphorylated p107 was the dominant form, in cells treated with other NSAIDs consistent with a G1 arrest. The ubiquitously expressed cyclin-dependent kinase (CDK) inhibitors, p21 and p27, were increased in all NSAID-treated cells. Our results suggest that diclofenac, indometacin, ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase, whereas the growth inhibitory effect of salicylates probably affects the late S and/or G2/M phases. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit in the treatment of certain vasculoproliferative disorders. [source]


    The role of the fibrocyte in intimal hyperplasia

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2006
    R. L. VARCOE
    Summary.,Background: Experimental animal studies have shown that the intimal hyperplasia (IH) responsible for occlusion after successful revascularization procedures may be partially caused by a bone marrow-derived cell that migrates to the site of vascular injury. Concurrent studies have demonstrated an extensive role in wound healing for the circulating fibrocyte. Objectives: We aimed to trace the path of the circulating cell that contributes to IH and determine if it is the fibrocyte. Methods and results: We established an in vitro model whereby purified monocytes from six healthy human volunteers were cultured into fibrocytes. These cells were morphometrically similar to the vascular smooth muscle cell (VSMC) found in IH and expressed alpha-smooth muscle actin (, -SMA) as well as CD34, CD45 and Collagen I (Col I), markers indicative of the fibrocyte. In an in vivo ovine carotid artery synthetic patch graft model, carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeled circulating leukocytes were observed throughout the graft as well as in the neointima in 18 sheep. These cells were shown to produce collagen and , -SMA at 1, 2 and 4 weeks. These cells then underwent immunohistochemical analysis and were found to express a set of markers unique to the fibrocyte (CD34, CD45, Vimentin and , -SMA) and also to double stain for CD34 and , -SMA. Conclusions: IH in an ovine carotid artery patch graft model is partially derived from a hematopoietic circulating progenitor cell that acquires mesenchymal features as it matures at the site of injury. [source]


    Vibration Causes Acute Vascular Injury in a Two-Step Process: Vasoconstriction and Vacuole Disruption

    THE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 8 2008
    Sandya R. Govindaraju
    Abstract Hand,arm vibration syndrome is a vasospastic and neurodegenerative occupational disease. In the current study, the mechanism of vibration-induced vascular smooth muscle cell (SMC) injury was examined in a rat-tail vibration model. Tails of male Sprague Dawley rats were vibrated continuously for 4 hr at 60 Hz, 49 m/s2 with or without general anesthesia. Ventral tail arteries were aldehyde fixed and embedded in epoxy resin to enable morphological analysis. Vibration without anesthesia caused vasoconstriction and vacuoles in the SMC. Anesthetizing rats during vibration prevented vasoconstriction and vacuole formation. Exposing tail arteries in situ to 1 mM norepinephrine (NE) for 15 min induced the greatest vasoconstriction and vacuolation. NE induced vacuoles were twice as large as those formed during vibration. When vibrated 4 hr under anesthesia after pretreatment with NE for 15 min, the SMC lacked vacuoles and exhibited a longitudinal banding pattern of dark and light staining. The extracellular matrix was filled with particulates, which were confirmed by electron microscopy to be cellular debris. The present findings demonstrate that vibration-induced vasoconstriction (SMC contraction) requires functioning central nervous system reflexes, and the physical stress of vibration damages the contracted SMC by dislodging and fragmenting SMC vacuoles. Anat Rec, 291:999,1006, 2008. © 2008 Wiley-Liss, Inc. [source]


    Reduction of vascular smooth muscle cell proliferation by immunomodulation

    BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 4 2001
    Y. C. Chan
    Background: Immunological factors may play an important role in mediating the progression of atherosclerosis and myointimal hyperplasia, with heat shock proteins being implicated as possible autoantigens. The authors have shown previously that immunomodulation can reduce vascular smooth muscle cell (vSMC) proliferation following balloon injury to rat carotid arteries. The aim of the present study was to examine the effects of immunomodulatory agents on the proliferation of rat aortic vSMCs remote from the area of balloon injury. The agents used were SRL172 (heat-killed Mycobacterium vaccae) and heat shock protein 65 kDa (HSP65) in Freund's incomplete adjuvant. Both these agents are known to influence T-cell responses. Methods: Male Sprague,Dawley rats were used. All immunizations were given subcutaneously. Four groups were studied (ten animals in each group): group 1 animals were immunized with normal saline, group 2 received SRL172, group 3 SRL172 and HSP65,Freund's, and group 4 HSP65,Freund's. Three immunizations were performed as well as carotid balloon injury. Three animals died, leaving 37 for analysis. Some 5 weeks later the animals were killed and the aorta was harvested. Standard explant techniques were applied to grow aortic vSMCs until confluency, passaged three times, quiesced, and fetal calf serum (FCS) of varying concentrations (0·4,10 per cent) was then added, incubated for another 48 h and cell counts carried out. Results: The proliferation rate of aortic vSMCs in the control group was significantly greater than that in the other study groups (Fig.). While all the treatment groups had significantly less proliferation compared with the control group (*P < 0·05, ,P < 0·01, Mann,Whitney U test), no statistically significant differences existed between any of the study groups. Conclusion: Immunomodulation may result in a reduction of vSMC proliferation. Although the precise mechanisms involved are unclear, these results are in concordance with previous findings that T-cell immunomodulation decreases the development of myointimal hyperplasia after injury, and suggest that a fundamental phenotypic shift has been produced by these immunizations. [source]


    Platelet-activating factor stimulates ovine foetal pulmonary vascular smooth muscle cell proliferation: role of nuclear factor-kappa B and cyclin-dependent kinases

    CELL PROLIFERATION, Issue 2 2008
    B. O. Ibe
    Objective: Platelet-activating factor (PAF) is implicated in pathogenesis of persistent pulmonary hypertension of the neonate (PPHN); PAF is a mitogen for lung fibroblasts. PAF's role in pulmonary vascular smooth muscle cell (PVSMC) proliferation and in hypoxia-induced pulmonary vein (PV) remodelling has not been established and mechanisms for PAF's cell-proliferative effects are not well understood. We investigated involvement of PAF and PAF receptors in PVSMC proliferation. Materials and methods: Cells from pulmonary arteries (SMC-PA) and veins (SMC-PV) were serum starved for 72 h in 5% CO2 in air (normoxia). They were cultured for 24 h more in normoxia or 2% O2 (hypoxia) in 0.1% or 10% foetal bovine serum with 5 µCi/well of [3H]-thymidine, with and without 10 nm PAF. Nuclear factor-kappa B (NF-,B), CDK2 and CDK4 protein expression, and their roles in cell proliferation control were studied. Results: PAF and hypoxia increased SMC-PA and SMC-PV proliferation. WEB2170 inhibited PAF-induced cell proliferation while lyso-PAF had no effect. SMC-PV proliferated more than SMC-PA and PAF plus hypoxia augmented NF-,B protein expression. NF-,B inhibitory peptide attenuated PAF-induced cell proliferation by 50% and PAF increased CDK2 and CDK4 protein expression. The data show that hypoxia and PAF up-regulate PVSMC proliferation via PAF receptor-specific pathway involving NF-,B, CDK2 and CDK4 activations. Conclusion: They suggest that in vivo, in foetal lung low-oxygen environment, where PAF level is high, proliferation of PVSMC will occur readily to modulate PV development and that failure of down-regulation of PAF effects postnatally may result in PPHN. [source]


    Redox-dependent signalling by angiotensin II and vascular remodelling in hypertension

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2003
    Rhian M Touyz
    Summary 1.,Hypertension is associated with structural alterations of resistance arteries, a process known as remodelling (increased media-to-lumen ratio). 2.,At the cellular level, vascular remodelling involves changes in vascular smooth muscle cell (VSMC) growth, cell migration, inflammation and fibrosis. These processes are mediated via multiple factors, of which angiotensin (Ang) II appears to be one of the most important in hypertension. 3.,Angiotensin II signalling, via AT1 receptors, is upregulated in VSMC from resistance arteries of hypertensive patients and rats. This is associated with hyperactivation of vascular NADPH oxidase, leading to increased generation of reactive oxygen species (ROS), particularly O2, and H2O2. 4.,Reactive oxygen species function as important intracellular second messengers to activate many downstream signalling molecules, such as mitogen-activated protein kinase, protein tyrosine phosphatases, protein tyrosine kinases and transcription factors. Activation of these signalling cascades leads to VSMC growth and migration, modulation of endothelial function, expression of pro-inflammatory mediators and modification of extracellular matrix. 5.,Furthermore, ROS increase intracellular free Ca2+ concentration ([Ca2+]i), a major determinant of vascular reactivity. 6.,All these processes play major roles in vascular injury associated with hypertension. Accordingly, ROS and the signalling pathways that they modulate provide new targets to regress vascular remodelling, reduce peripheral resistance and prevent hypertensive end-organ damage. 7.,In the present review, we discuss the role of ROS as second messengers in AngII signalling and focus on the implications of these events in the processes underlying vascular remodelling in hypertension. [source]


    The death of cardiotonic steroid-treated cells: evidence of Na+i,K+i -independent H+i -sensitive signalling

    ACTA PHYSIOLOGICA, Issue 1-2 2006
    S. N. Orlov
    Abstract Na/K-ATPase is the only known target of cardiotonic steroids (CTS) identified in plants, amphibians and later on in several mammalian species, including human. We focus our review on recent data implicating CTS in the tissue-specific regulation of cell survival and death. In vascular smooth muscle cells, CTS inhibited cell death triggered by apoptotic stimuli via a novel Na+i -mediated, Ca2+i -independent mechanism of expression of antiapoptotic genes, including mortalin. In contrast, exposure to CTS in vascular endothelial and renal epithelial cells led to cell death, showing combined markers of apoptosis and necrosis. This mode of cell death, termed oncosis, is caused by CTS interaction with Na/K-ATPase but is independent of the inhibition of Na/K-ATPase-mediated ion fluxes and inversion of the [Na+]i/[K+]i ratio. The intermediates of intracellular signalling involved in Na+i, K+i -independent oncosis of CTS-treated cells remain unknown. Recently, we found that this mode of cell death can be protected by modest intracellular acidification via the expression of H+i -sensitive genes. The molecular origin of intracellular Na+ and H+ sensor involvement in the development of apoptosis and oncosis is currently under investigation. [source]


    Plectin deposition at podosome rings requires myosin contractility

    CYTOSKELETON, Issue 8 2008
    Annica Gad
    Abstract Metalloproteinase-dependent tissue invasion requires the formation of podosomes and invadopodia for localized matrix degradation. Actin cytoskeleton remodeling via Arp2/3-mediated actin polymerization is essential for podosome formation, and dynamic microtubules have an important role in maintaining podosome turnover in macrophages and osteoclasts. Little is known, however, about the involvement of the intermediate filament cytoskeleton in formation, stabilization, and turnover of podosomes. Here we show that vimentin intermediate filaments colocalize with the early sites of podosome formation at the stress fiber - focal adhesion interface in cultured vascular smooth muscle cells, but do not directly contribute to podosome formation, or stabilization. In unstimulated A7r5 cells the cytolinker protein plectin poorly colocalized with vimentin and the microdomains, but following induction by phorbol ester accumulated in the rings that surround the podosomes. In plectin-deficient A7r5 cells actin stress fiber remodelling is reduced in response to PDBu, and small podosomes remain localized at stable actin stress fibres. Pharmacological inhibition of actomyosin contractility by blebbistatin leads to an aberrant localization of podosomes away from the cell periphery and induces failure of plectin to surround the outer perimeter of these invasive adhesions. Taken together, we conclude that plectin is involved in growth and maturation of podosomes by reducing focal adhesion and stress fiber turnover, and that actomyosin-dependent contractility is required for the peripheral localization and specific deposition of plectin at the podosome rings. Cell Motil. Cytoskeleton 2008. © 2008 Wiley-Liss, Inc. [source]


    Platelet-derived growth factors in the developing avian heart and maturating coronary vasculature

    DEVELOPMENTAL DYNAMICS, Issue 4 2005
    Nynke M.S.
    Abstract Platelet-derived growth factors (PDGFs) are important in embryonic development. To elucidate their role in avian heart and coronary development, we investigated protein expression patterns of PDGF-A, PDGF-B, and the receptors PDGFR-, and PDGFR-, using immunohistochemistry on sections of pro-epicardial quail,chicken chimeras of Hamburger and Hamilton (HH) 28,HH35. PDGF-A and PDGFR-, were expressed in the atrial septum, sinus venosus, and throughout the myocardium, with PDGFR-, retreating to the trabeculae at later stages. Additionally, PDGF-A and PDGFR-, were present in outflow tract cushion mesenchyme and myocardium, respectively. Small cardiac nerves and (sub)epicardial cells expressed PDGF-B and PDGFR-,. Furthermore, endothelial cells expressed PDGF-B, while vascular smooth muscle cells and interstitial epicardium-derived cells expressed PDGFR-,, indicating a role in coronary maturation. PDGF-B is also present in ventricular septal development, in the absence of any PDGFR. Epicardium-derived cells in the atrioventricular cushions expressed PDGFR-,. We conclude that all four proteins are involved in myocardial development, whereas PDGF-B and PDGFR-, are specifically important in coronary maturation. Developmental Dynamics 233:1579,1588, 2005. © 2005 Wiley-Liss, Inc. [source]


    The pharmacology of cilostazol

    DIABETES OBESITY & METABOLISM, Issue 2002
    Karsten Schrör
    Cilostazol (6-[4-(1-cyclohexyl- 1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 µm). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration. [source]


    Sphingosine-1-phosphate and FTY720 as anti-atherosclerotic lipid compounds

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2007
    M. Tölle
    Abstract All stages of atherosclerosis have been identified as a chronic vascular inflammatory disease. In the last few years there is increasing evidence that endogenous lysophospholipids such as sphingosine-1-phosphate (S1P) have potent anti-inflammatory properties. The S1P analogue FTY720 that has been developed as a potent, orally active, immunosuppressant in the field of transplantation and autoimmune disease has interesting effects on inflammatory processes in the arterial vessel wall. S1P targets five specific S1P receptors (S1P1,5), which are ubiquitously expressed. S1P1,3 receptor expression is identified in arterial vessels. S1P and FTY720 show potent silencing effects on some vascular proinflammatory mechanisms in endothelial and vascular smooth muscle cells. In addition, the interaction of monocytes with the vessel wall is inhibited. As shown recently, FTY720 can effectively reduce the progression of atherosclerosis in apolipoprotein E-deficient mice having a high-cholesterol diet. It is not entirely clear which S1P receptor subtype is mainly involved in this process. However, it is currently speculated that the S1P3 and probably the S1P1 is involved in the anti-atherosclerotic effects of FTY720. This review summarizes the current knowledge about S1P- and FTY720-effects on mechanisms of vascular inflammatory disease. In addition S1P receptor subtypes are identified which might be interesting for molecular drug targeting. [source]


    Mechanical stretch induces TGF-, synthesis in hepatic stellate cells

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2004
    R. Sakata
    Abstract Background, It is known that mechanical stress induces extracellular matrix via transforming growth factor-, (TGF-,) synthesis in vascular smooth muscle cells. Activated hepatic stellate cells (HSCs) are an important source of TGF-, in the liver. However, it remains unclear whether mechanical stress induces TGF-, in HSCs. The Rho small GTP-binding protein (Rho) has recently emerged as an important regulator of actin and cytoskeleton. We examined whether TGF-, is expressed in stretched HSCs and whether Rho is involved in stretch-induced TGF-, synthesis. Materials and methods, A cultured human HSC cell line, LI90, was used for this study. Hepatic stellate cells were cyclically stretched using the Flexercell® strain unit. Concentration of TGF-, in the conditioned medium was estimated by a bioassay using mink lung epithelial cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Transforming growth factor-, mRNA expression of HSCs was estimated by a reverse-transcription polymerase chain reaction. Replication-defective adenoviral vectors expressing a dominant negative type of Rho was utilized to suppress its effect on HSCs. Results, Transforming growth factor-, concentration of the conditioned media of stretched HSCs showed time-dependent increases as compared to nonstretched HSCs from 2 h to 24 h. Transforming growth factor-, mRNA expression in stretched HSCs was increased compared with that in nonstretched HSCs. Transfection of dominant negative Rho inhibited the stretch-induced TGF-, synthesis. Conclusions, Mechanical stretch enhanced TGF-, expression on mRNA and protein level in HSCs. Rho was closely related to stretch-induced TGF-, synthesis in HSCs. [source]


    Enhanced survival of vascular smooth muscle cells accounts for heightened elastin deposition in arteries of neonatal spontaneously hypertensive rats

    EXPERIMENTAL PHYSIOLOGY, Issue 4 2010
    Silvia M. Arribas
    Abnormal stiffening and narrowing of arteries are characteristic features of spontaneously hypertensive rats (SHR). In this strain, we have previously demonstrated an increased elastin content and abnormal organization of lamellae in conduit and resistance arteries from neonatal rats that preceded the impending inward remodelling, increased vascular stiffness and development of hypertension. The aim of this study was to assess the mechanism responsible for such excessive and aberrant elastin deposition in SHR vessels during perinatal development. We compared elastin, collagen and fibronectin production (inmunocytochemistry and quantitative assay of metabolically labelled insoluble elastin), DNA content as well as cell proliferation (proliferative cellular nuclear antigen, bromodeoxyuridine incorporation) and death rates (propidium iodide exclusion test, terminal transferase nick and labeling (TUNEL) assay) in cultures of vascular smooth muscle cells (VSMC) derived from neonatal SHR and Wistar,Kyoto (WKY) control rats. Cultures of VSMC derived from neonatal SHR exhibited hypertrophy, produced more elastin, collagen and fibronectin and contained more DNA than equally plated WKY counterparts. Further analysis revealed that the higher net DNA content in SHR-derived cultures was due to increased diploidy, but not to a heightened cell multiplication. The SHR-derived VSMC also exhibited lower rates of cell death and apoptosis, which were associated with increased levels of the anti-apoptotic protein, survivin. We therefore conclude that the peculiar heightened survival of matrix-producing VSMC in neonatal SHR is responsible for accumulation of hard-wearing elastin and other extracellular matrix elements in the growing arteries, thereby contributing to the subsequent development of systemic hypertension. [source]


    Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts

    EXPERIMENTAL PHYSIOLOGY, Issue 5 2008
    Jodie L. Guy
    The renin,angiotensin system (RAS), in particular angiotensin II, plays an important role in cardiac remodelling. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key players in the RAS and act antagonistically to regulate the levels of angiotensin II. In this study, we reveal the functional expression of ACE2 in human cardiac myofibroblasts, cells that are essential to the maintenance of normal cardiac architecture and also play a key role in myocardial remodelling. The observed reciprocal expression of ACE and ACE2 in these cells may reflect the possible opposing activity of these two enzymes. In this study, we demonstrate the presence of ACE2 as an ectoenzyme and reveal that ACE2 undergoes phorbol-12-myristate-13-acetate-inducible ectodomain shedding from the membrane. When cells were exposed to a number of pathophysiological stimuli, modulation of ACE2 levels was not detected. Importantly, whilst we found ACE2 to be expressed constitutively in cardiac myofibroblasts there were no detectable levels in either vascular smooth muscle cells or vascular endothelium, indicating that ACE2 expression is not ubiquitous. In paraffin sections of atrial appendage tissue, we observed a distinct staining pattern for ACE2 which appeared different from that of ACE. In conclusion, this study is the first to report co-expression of ACE and ACE2 in human cardiac myofibroblasts and may therefore present a model primary system for study of the comparative cell biology of ACE2 and ACE and their potentially opposing roles in myocardial remodelling. [source]


    [Na+]i -induced c-Fos expression is not mediated by activation of the 5,-promoter containing known transcriptional elements

    FEBS JOURNAL, Issue 14 2007
    Mounsif Haloui
    In vascular smooth muscle cells and several other cell types, inhibition of Na+/K+ -ATPase leads to the expression of early response genes, including c-Fos. We designed this study to examine whether or not a putative Na+i/K+i -sensitive element is located within the c-Fos 5,-UTR from ,,650 to +,103 containing all known response elements activated by ,classic' stimuli, such as growth factors and Ca2+i -raising compounds. In HeLa cells, the highest increment of c-Fos mRNA content was noted after 6 h of Na+/K+ -ATPase inhibition with ouabain that was abolished by actinomycin D, an inhibitor of RNA synthesis. c-Fos protein accumulation in ouabain-treated cells correlated with a gain of Na+i and loss of K+i. Augmented c-Fos expression was also observed under inhibition of Na+/K+ -ATPase in K+ -free medium and in the presence of the Na+ ionophore monensin. The effect of ouabain on c-Fos expression was sharply attenuated under dissipation of the transmembrane Na+ gradient, but was preserved in the presence of Ca2+ chelators and the extracellular regulated kinase inhibitor PD98059, thus indicating an Na+i -mediated, Ca2+i - and extracellular regulated kinase-independent mechanism of gene expression. In contrast to massive c-Fos expression, we failed to detect any effect of ouabain on accumulation of luciferase driven by the c-Fos 5,-UTR. Negative results were also obtained in ouabain-treated vascular smooth muscle cells and C11 Madin,Darby canine kidney cells possessing augmented c-Fos expression. Our results reveal that Na+i -induced c-Fos expression is not mediated by the 5,-UTR containing transcriptional elements activated by growth factors and other ,classic stimuli'. [source]


    Context-specific regulation of LINE-1

    GENES TO CELLS, Issue 10 2007
    Ivo Teneng
    The present study was conducted to evaluate the contextual specificity of long interspersed nuclear element-1 (LINE-1 or L1) activation by cellular stress and the role of the aryl hydrocarbon receptor (AHR) transcription factor and oxidative stress in the gene activation response. Activation of the AHR by the genotoxic carcinogen benzo(a)pyrene (BaP) increased L1 expression in human cervical carcinoma (HeLa) cells, human microvascular endothelial cells (HMEC), mouse vascular smooth muscle cells (mVSMC) and mouse embryonic kidney cells (mK4). In contrast, challenge with a different AHR ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), or UV irradiation (10,20 J/m2), induced L1 only in HeLa cells. Transactivation of the mouse L1Md-A5 promoter was observed in all cell types challenged with BaP, while TCDD was without effect, and UV only activated L1 in HeLa cells. Genetic and pharmacological experiments implicated the AHR and oxidative stress as contextual determinants of L1 inducibility by cellular stress. [source]


    Suppression of NF-,B-dependent gene expression by a hexamethylene bisacetamide-inducible protein HEXIM1 in human vascular smooth muscle cells

    GENES TO CELLS, Issue 2 2003
    Rika Ouchida
    Background: Neointima formation is a characteristic feature of atherosclerosis and post-angioplasty restenosis, in which various soluble factors and mechanical injury stimulate signalling pathways in vascular smooth muscle cells (VSMC), promoting their migration and proliferation, and the eventual formation of the neointima. The transcription factor NF-,B has been shown to play a pivotal role in this process. Hexamethylene bisacetamide, an inhibitor of VSMC proliferation, induces the mRNA expression of HEXIM1 (hexamethylene bisacetamide-inducible protein 1). However, the protein expression and function of HEXIM1 remain unknown. Results: In the present study, we demonstrated that HEXIM1 localizes in the cytoplasm and nucleus, and its nuclear expression is restricted to discrete speckled areas. Treatment of VSMC with hexamethylene bisacetamide up-regulated HEXIM1 expression, not only in mRNA but also protein levels. Moreover, HEXIM1 is shown to suppress the transcriptional activity of NF-,B via its C-terminal leucine-rich domain. A glutathione-S-transferase pull down assay indicated that HEXIM1 interacts with the p65 subunit of NF-,B. In VSMC, treatment with hexamethylene bisacetamide resulted in a down-modulation of the transcription of NF-,B target genes. Conclusion: We may therefore conclude that HEXIM1 plays an inhibitory role in NF-,B-dependent gene expression in VSMC and is the candidate of a novel therapeutic target for inhibition of VSMC proliferation. [source]