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Results for “Phenotypic modulation”

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PubMed2000

Transplant atherosclerosis: role of phenotypic modulation of vascular smooth muscle by nitric oxide.

Occlusive accelerated atherosclerosis of coronary grafts is the predominant factor that limits longevity of heart transplant recipients. This form of vascular disease affects both the large epicardial and the smaller intramyocardial vessels, leading to characteristic clinical presentation that necessitates the use of sophisticated techniques for their accurate detection. Accelerated atherosclerosis after transplantation is a multifactorial disease with many events contributing to its progression. The initial vascular injury associated with ischemia-reperfusion appears to aggravate preexisting conditions in the donor vasculature in addition to activation of new immunological and nonimmunological mechanisms. Throughout these events, the endothelium remains a primary target of cell- and humoral-mediated injury. Changes in the vascular intima leads to alterations in vascular smooth muscle cell (VSMC) physiology, resulting in VSMC phenotypic modulation with the orchestration of a broad spectrum of growth and inflammatory reactions, which might be a healing response to vascular injury. Endogenous nitric oxide (NO) pathways regulate a multiplicity of cellular mechanisms that play a major role in determining the structure and function of the vessel wall during normal conditions and during remodeling associated with accelerated atherosclerosis. Recently identified signaling pathways, including mitogen-activated protein kinase, cGMP-dependent protein kinase, phosphatidylinositol 3-kinase, and transcriptional events in which nuclear factor kappa B and activator protein 1 take part, can be associated with NO modulation of cell cycle perturbations and phenotypic alteration of VSMC during accelerated atherosclerosis. This article reviews recent progress covering the aforementioned matters. We start by summarizing the clincal aspects and pathogenesis of accelerated atherosclerosis associated with transplantation, including clinical presentation and detection. This summary is followed by a discussion of the multiple factors of the disease process, including immunological and nonimmunolgical contributions. The next section focuses on cellular responses of the VSMCs relevant to lesion formation, with special emphasis on classical and recent paradigms of phenotypic modulation of these cells. To examine the influence of NO on VSMC phenotypic modulation and consequent lesion development, we briefly overview characteristics of NO production in the normal coronary vascular bed and the changes in endogenous NO release and activity during atherosclerosis. This overview is followed by a section covering molecular mechanisms whereby NO regulates a range of signaling pathways, transcriptional events underlying cell cycle perturbation, and phenotypic alteration of VSMC in accelerated atherosclerosis.

Animals↗

PubMed2001

Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids.

The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the differentiated state to the dedifferentiated one is critically involved in the development and progression of atherosclerosis. Although many cytokines and growth factors have been reported as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for visceral SMCs and VSMCs in which both SMCs, when cultured on laminin with insulin-like growth factor-I, show a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level of SMC differentiation marker gene expression. In this study, we searched for critical dedifferentiation factors for these SMCs using our culture system. We found that polar lipids extracted from human serum markedly induced VSMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors to the induction of VSMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced VSMC dedifferentiation is mediated through the coordinated activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Thus, this report demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce VSMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.

Animals↗

PubMed1997

Differential expression of mRNAs for endopeptidases in phenotypically modulated ('dedifferentiated') human articular chondrocytes.

Human articular chondrocytes modulated away from their original phenotype by serial subcultures in monolayer differentially express mRNAs for endopeptidases. The mRNAs for the cathepsins B and L are extremely low in differentiated cells, but are soon expressed in parallel with the loss of the differentiated state. In contrast, the mRNA for collagenase-1 is strongly expressed by differentiated chondrocytes and declines rapidly following phenotypic modulation. The mRNA for stromelysin-1 and the tissue inhibitor of metalloproteinases-2 is high and does not appreciably change after modulation. Chondrocyte activation induced by alteration of its original phenotype leads to the expression of endopeptidases in a way that markedly differs from that induced by cytokines. The results are relevant to cartilage catabolism in osteoarthritis and suggest a prominent role of fibroblastic metaplasia on the part of the chondrocytes as a mechanism of expressing catabolic endopeptidases.

Adult↗

PubMed1998

Phenotype modulation in primary cultures of aortic smooth muscle cells from streptozotocin-diabetic rats.

Diabetes mellitus is a major risk factor for atherosclerosis. In atherosclerotic lesions, arterial smooth muscle cells (SMC) change from a contractile to a synthetic phenotype characterized by active proliferation. A similar phenotype modulation occurs in vitro when isolated arterial SMC are grown in culture and is characterized by both changes in cell morphology and a typical switch in actin isoform expression. In this study, we examined the influence of streptozotocin (STZ)-induced diabetes on the differentiation state and the phenotype modulation of cultured rat aortic SMC. We used transmission electron microscopy to study the fine structure of STZ-diabetic and non-diabetic SMC in primary culture and immunological methods for the determination of the proportions of alpha-smooth muscle actin (alpha-SM) and nonmuscle beta-actin (beta-NM) isoforms. Cultured STZ-diabetic SMC exhibited a large cytoplasmic volume, rich in rough endoplasmic reticulum, when compared with cultured non-diabetic SMC. alpha-SM, organized in stress fibers, was less homogeneously and abundantly distributed and by contrast, beta-NM was more abundant in STZ-diabetic than in non-diabetic SMC. Cytofluorimetric analyses demonstrated that the alpha-SM content was reduced in freshly STZ-diabetic SMC. Furthermore, during logarithmic growth of cultured SMC, the decrease of alpha-SM was more important in STZ-diabetic than in non-diabetic SMC. Immunoblotting of actin isoforms confirmed that expression of beta-NM was more important in STZ-diabetic than in non-diabetic SMC even in freshly isolated cells. The results suggest that SMC from STZ-diabetic rats express a more dedifferentiated state and undergo a more rapid phenotypic modulation in primary cultures than SMC from non-diabetic rats. Therefore, diabetes could induce changes in the phenotype of arterial SMC which might be associated with the onset or progression of the atherogenic process.

Actins↗

PubMed1990

Collagen synthesis by cultured arterial smooth muscle cells during spontaneous phenotypic modulation.

Quantitative and qualitative changes in collagen synthetic activity by rabbit arterial smooth muscle cells were monitored during spontaneous phenotypic modulation from days 2-15 of culture. The cultured smooth muscle cells transformed into a synthetic phenotype, reaching a maximum of 94.6% on day 4, and then gradually returned to a contractile phenotype accounting for 59.3% on day 15 of culture. The maximum collagen synthesis was found on day 7 when the cells were in early quiescent phase and showed a 91.7% synthetic phenotype. With an increasing proportion of cells in a contractile state, total collagen synthesis per cell decreased in parallel with the reduction in total protein synthesis. Synthesis of type I collagen was predominant, and the proportion of type I + III collagen was over 85% during the entire period of culture. Synthetic activity of type IV collagen, however, was relatively increased, and reached 3.8 +/- 0.4% at day 15 in comparison with 0.8 +/- 0.1% in the late logarithmic growth phase on day 4. This significant increment of type IV collagen in vitro seems to be correlated with the phenotypic modulation of cultured smooth muscle cells into a contractile phenotype.

Animals↗

PubMed2004

Fluvastatin prevents vascular hyperplasia by inhibiting phenotype modulation and proliferation through extracellular signal-regulated kinase 1 and 2 and p38 mitogen-activated protein kinase inactivation in organ-cultured artery.

OBJECTIVE: We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured rat tail artery. METHODS AND RESULTS: After 5 days of culture with 10% FBS, hyperplastic morphological changes in the media layer were induced. Treatment with 1 mumol/L fluvastatin significantly inhibited these changes. In the FBS-cultured arteries, the protein expression ratio of alpha-actin/beta-actin was significantly decreased, indicating the change to synthetic phenotype. Fluvastatin restored the decreased expression ratio, and the addition of mevalonate (100 mumol/L) suppressed this recovery. In accordance with the synthetic morphological changes, the absolute force of contractions induced by stimuli was decreased. Fluvastatin treatment also restored the decreased contractility, and the addition of mevalonate suppressed this recovery. In the arteries cultured with FBS, extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation were significantly increased. Fluvastatin inhibited these phosphorylations, and mevalonate prevented the action of fluvastatin. CONCLUSIONS: These results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation to synthetic phenotype and proliferation by inhibiting the local metabolic pathway of cholesterol in smooth muscle cells, which inhibits hyperplastic changes in the vascular wall. The antihyperplastic actions by statins may be induced by inhibiting the ERK1/2 and p38MAPK activities, possibly through inhibition of prenylated Ras. We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured artery. Results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation and proliferation by inhibiting the ERK1/2 and p38MAPK activities through depletion of mevalonate in smooth muscle cells, resulting in inhibiting vascular hyperplastic changes.

Animals↗

PubMed1999

Association of smooth muscle cell phenotypic modulation with extracellular matrix alterations during neointima formation in rabbit vein grafts.

PURPOSE: To clarify the mechanisms of structural changes underlying vein graft stenosis that limits efficacy of bypass grafting operation, we examined the accumulation and distribution of various extracellular matrix (ECM) components during neointima formation in rabbit vein grafts and analyzed their correlation with proliferation and phenotypic modulation of smooth muscle cells (SMCs). METHODS AND RESULTS: An autologous external jugular vein graft was transplanted into the carotid artery in 25 rabbits. After the restoration of blood flow, the graft was markedly dilated. Medial SMCs in the graft appeared to be injured, and they began to proliferate at day 4 and subsequently migrated and formed the neointima at day 7. The neointima observed at days 7 and 14 contained ECM components, including type I collagen, heparan sulfate, and chondroitin sulfate, and the intimal SMCs were phenotypically modulated from the differentiated-type (SM2-positive and SM embryonic-negative) to the dedifferentiated-type (SM2-negative and SM embryonic-positive) as determined with immunostainings for myosin heavy chain isoforms. The intimal SMC proliferation was maximal at 2 weeks and then decreased rapidly. However, the neointima continued to thicken thereafter throughout the 6-month period of the experiment, and ECM accumulation, such as type I collagen and decorin, a small dermatan sulfate proteoglycan, was a prominent feature observed in the hypocellular region of the deep intima from 2 months after the transplantation. The phenotype of the intimal SMCs gradually returned to the differentiated-type from the deep intima after 2 months, but a small number of the intimal SMCs remained in the dedifferentiated phenotype even at 6 months after the operation. CONCLUSION: The neointima in the vein graft was formed initially by means of migration and proliferation of the phenotypically modulated, dedifferentiated-type SMCs and continued to thicken by means of sustained ECM accumulation, including type I collagen and decorin, in association with the prolonged presence of the dedifferentiated-type SMCs. These chronologic features in cell kinetics and ECM accumulation may contribute to the frequent occurrence of graft wall thickening that occurs in the vein grafts.

Animals↗

PubMed2006

Synergistic roles of platelet-derived growth factor-BB and interleukin-1beta in phenotypic modulation of human aortic smooth muscle cells.

The phenotype of smooth muscle cells (SMCs) plays an important role in vascular function in health and disease. We investigated the mechanism of modulation of SMC phenotype (from contractile to synthetic) induced by the synergistic action of a growth factor (platelet-derived growth factor, PDGF-BB) and a cytokine (interleukin, IL-1beta). Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle alpha-actin, myosin heavy chain, and calponin). These levels were not significantly affected by PDGF-BB and IL-1beta individually, but decreased markedly after the combined usage of PDGF-BB and IL-1beta. PDGF/IL-1beta costimulation also induced a sustained phosphorylation of Akt and p70 ribosomal S6 kinase (p70S6K). The effects of PDGF/IL-1beta costimulation on contractile marker expression and Akt and p70S6K phosphorylation were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 and by adenovirus expressing a dominant-negative Akt, and they were mimicked by constitutively active Akt. PDGF-BB/IL-1beta induced a sustained phosphorylation of PDGF receptor (PDGFR)-beta and its association with IL-1 receptor (IL-1R1). Such activation and association of receptors were blocked by a PDGFR-beta neutralizing antibody (AF385), an IL-1R1 antagonist (IL-1ra), as well as a specific inhibitor of PDGFR-beta phosphorylation (AG1295); these agents also eliminated the PDGF-BB/IL-1beta-induced signaling and phenotypic modulation. PDGF-BB/IL-1beta inhibited the polymerized collagen-induced serum response factor DNA binding activity in the nucleus, and this effect was mediated by the PDGFR-beta/IL-1R1 association and phosphatidylinositol 3-kinase/Akt/p70S6K pathway. Our findings provide insights into the mechanism of SMC phenotypic modulation from contractile to synthetic, e.g., in atherosclerosis.

Aorta↗

PubMed2005

Phosphatidylinositol 3-kinase/Akt pathway is involved in transforming growth factor-beta1-induced phenotypic modulation of 10T1/2 cells to smooth muscle cells.

Transforming growth factor-beta1 (TGF-beta1) is known to induce phenotypic modulation of mesenchymal cells to SMCs. However, the intracellular signals regulating induction of the SMC phenotype of mesenchymal cells have not been fully clarified. In the present study, we examined the role of the mitogen-activated protein kinase (MAPK) superfamily and phosphatidylinositol 3-kinase (PI3K)/Akt in the TGF-beta1-mediated phenotypic modulation of 10T1/2 mesenchymal cells to SMCs characterized by the expression of SMC-specific markers, including smooth muscle alpha-actin (SMalpha-actin), myosin heavy chain (SM-MHC), and protein 22-alpha (SM22alpha). The results showed the following: (1) TGF-beta1 induced SMalpha-actin and SM-MHC expressions in 10T1/2 cells in a time-dependent manner. (2) TGF-beta1 induced biphasic increases in extracellular signal-regulated kinase (ERK), p38 MAPK, c-Jun-NH2-terminal kinase (JNK), and Akt phosphorylation. (3) The inhibitor for PI3K/Akt (i.e., LY294002), but not those for MAPKs (i.e., SB203580, PD98059, and SP600125), attenuated the TGF-beta1-induced SMalpha-actin and SM-MHC expressions in 10T1/2 cells; in addition, transfection of 10T1/2 cells with the Akt-specific small interfering RNA (siRNA) significantly reduced their SMalpha-actin and SM-MHC expressions. (4) LY294002 and the Akt-specific siRNA inhibited the TGF-beta1-induced SM22alpha gene expression and promoter activity, suggesting that the TGF-beta1-induced gene expression was mediated by PI3K/Akt at the transcriptional level. (5) LY294002 inhibited the TGF-beta1-induced gene expression and DNA binding activity of serum response factor (SRF). These results indicate that TGF-beta1 is capable of inducing the SMC phenotype of 10T1/2 cells and that this induction is mediated through the PI3K/Akt signaling pathway.

Actins↗

PubMed1993

The role of vascular smooth muscle cell phenotypic modulation at the aortic branch in atherogenesis.

To elucidate the mechanism of the development of atherosclerosis, we have investigated the cell population of phenotypes of contractile (C-SMC) and synthetic (S-SMC) states of SMCs at proximal and distal areas of bifurcation of the celiac and superior mesenteric arteries in children and young persons by transmission electron microscopy. The previous studies in patients with hypercholesterolemia and who were young indicated that percentages of proximal area at bifurcation of both arteries were greater than that of C-SMC (P 0.01), and that C-SMCs at distal area were less than that of S-SMC (P 0.05). Ultrastructurally, SMCs at proximal area were S-SMCs containing many synthetic organelles and intermediate filaments. On the other hand, those at distal area were C-SMCs containing actin, myosin, dense bodies and microtubules. In the present study, we have ascertained that the phenotypic modulation of SMCs in the intima and media might correlate to the physico-medial relationship between SMCs and elastic tissues. In this communication, we have observed that the intimal SMCs transformed their phenotypes from the internal elastic layer (S-SMC) to the superficial layer (C-SMC), and that the medial SMCs in the arteries of the young clearly consisted of two types: one type adhered to the elastic layer and the other type existed with the separated one. The difference between both areas in the relatively young need to be observed in detail from now on. In summary, the vascular SMCs and the elastic lamina are considered to contribute to the subsequent phenotypic modulation and their migration of SMCs.

Adolescent↗

PubMed2005

Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5.

Modulation of smooth muscle cell (SMC) phenotype plays a central role in neointima formation. We recently demonstrated that Am80, a synthetic retinoic acid receptor alpha-specific agonist, inhibits the activity of the transcription factor KLF5, which is essential for neointima formation after vascular injury. In the present study, we aimed to further analyze the mechanism by which Am80 inhibits KLF5 and the effects of inhibiting KLF5 on SMCs and vascular lesion formation, as well as to evaluate potential of Am80 for use in the prevention of in-stent neointima formation. We found that Am80 inhibited both the expression and transcriptional function of KLF5. Of particular interest was our finding that KLF5 forms a transcriptionally active complex with unliganded RAR/RXR heterodimer on the PDGF-A promoter; Am80 disrupts this complex, thereby inhibiting KLF5-dependent transcriptional activation. Knocking down KLF5 using small interfering RNA suppressed serum-induced downregulation of SMC differentiation marker gene expression in cultured SMCs, and haploinsufficiency of KLF5 in mice attenuated phenotypic modulation of SMCs after vascular injury, indicating that KLF5 plays a key role in the control of SMC phenotype. Am80 augmented expression of the SMC differentiation marker genes in culture and within the vessel walls, and oral administration of Am80 significantly inhibited in-stent neointima formation in a rabbit stent-placement model. Taken together, these results demonstrate that KLF5 plays an important role in the control of SMC phenotype after vascular injury and suggest the feasibility of using Am80, delivered systemically and/or with a drug eluting stent, to prevent in-stent neointima formation.

Actins↗

PubMed2003

Phenotypic modulation of cultured bladder smooth muscle cells and the expression of inducible nitric oxide synthase.

Phenotypic modulation of smooth muscle is associated with various pathological conditions, including bladder dysfunction. Cytoskeletal dynamics modulate the cell phenotype and were recently shown to be involved in regulation of inducible nitric oxide synthase (iNOS). We tested the hypothesis that the cell differentiation status affects iNOS expression, and that iNOS is preferentially expressed in immature dedifferentiated bladder smooth muscle cells (BSMC). Isolated at BSMC were put into different stages of differentiation by serum deprivation on laminin-coated plates in the presence of IGF-I and by interaction with Rho signaling and actin polymerization. iNOS and smooth muscle-myosin heavy chain (SM-MHC) protein expression were investigated with Western blot analysis. Our results showed iNOS protein in BSMC exposed to interleukin-1 beta (2 ng/ml) + TNF-alpha (50 ng/ml). Growth of BSMC in serum-free medium on laminin in the presence of IGF-I increased SM-MHC expression, whereas cytokine-induced iNOS was inhibited. Disruption of F-actin with latrunculin B (0.5 microM) potentiated iNOS expression and decreased SM-MHC expression. Rho inhibition with C3 (2.5 microg/ml) increased iNOS expression, whereas SM-MHC expression was slightly decreased. Rho-kinase inhibition with Y-27632 (10 microM) mediated a decrease in iNOS and a slight increase in SM-MHC expression. In conclusion, the capacity of BSMC to express iNOS was negatively correlated to differentiation status measured as SM-MHC expression. Actin cytoskeletal dynamics and Rho signaling are involved in regulation of cytokine-induced iNOS expression in BSMC. Phenotypic changes and impairment in actin cytoskeleton formation may potentiate cytokine activation and in turn increase nitric oxide production in the bladder during disease.

Actins↗

PubMed1991

The role of vascular smooth-muscle cells in atherogenesis: phenotypic modulation of the medial smooth-muscle cells in the aortic bifurcation.

To elucidate the mechanism of migration of vascular smooth-muscle cells (SMCs) from media to intima, we have investigated the phenotypic modulation of the medial SMC at bifurcation of the celiac artery in 5 children and 3 young persons using a transmission electron microscope. We counted the number of separated SMCs from the elastic layers, although the medial SMCs are fundamentally attached to the elastic fibers, and are still contractile in their phenotypes. Both proximal and distal portions revealed that SMCs in the media were more or less present in the separated state and were ultrastructurally consistent with the synthetic state of SMC in the proximal area and the contractile state in distal areas. In order to migrate from media to intima, medial SMC should separate from the elastic layers and transform their phenotypes. In this paper, we examined the relationship between vascular SMCs and elastic layers in the media and ascertain that it was responsible for the contribution to the subsequent phenotypic modulation and their migration of medial SMCs.

Adolescent↗

PubMed2002

Smoothelin is an indicator of reversible phenotype modulation of smooth muscle cells in balloon-injured rat carotid arteries.

Restenosis is the major obstacle interfering with a successful long-term outcome of balloon angioplasty. Neointima formation following endothelial injury is the result of phenotype modulation and proliferation of smooth muscle cells (SMC). To characterize these time-dependent changes, a rat balloon injury model of carotid artery restenosis was assessed. We applied monoclonal antibodies recognizing desmin, sm-alpha-actin and smoothelin, a novel marker specific for the differentiated phenotype of SMC. Neointima formation could be seen from day 7 after injury onwards. During early phases, the number of smoothelin-positive cells in the media was decreased compared with uninjured controls. Smoothelin staining was absent in the neointima during formation. Increased levels of smoothelin in both media and neointima were observed at days 28 and 56, correlating with a decrease in proliferation as assessed by Ki-67 antigen staining. No such changes were observed for desmin and sm-alpha-actin. Following balloon injury, SMC in both the media and the neointima underwent an early, reversible dedifferentiation, followed by proliferation. The novel SMC-specific marker protein smoothelin can be used to monitor this SMC (de)differentiation in neointima and media. These findings support the pivotal role of SMC phenotype modulation in neointima formation and restenosis.

Actins↗

PubMed2004

A role for chemokines in the induction of chondrocyte phenotype modulation.

OBJECTIVE: To extend the study of the chemokine receptor repertoire on human chondrocytes to receptors with reported housekeeping functions (CXCR3, CXCR4, CXCR5, and CCR6) and to evaluate whether ligands of these receptors play a role in chondrocyte phenotype modulation and proliferation. METHODS: Chemokine receptor expression was determined by flow cytometry. Subcultures of chondrocytes were collected and fixed at confluence or during the exponential phase of growth and analyzed for chemokine receptor modulation. The effects of chemokines on isolated cells as well as chondrocytes cultured within an intact extracellular matrix were investigated. Isolated human chondrocytes were stimulated with 100 nM chemokines (monokine induced by interferon-gamma, stromal cell-derived factor 1alpha [SDF-1alpha], B cell-attracting chemokine 1 [BCA-1], or macrophage inflammatory protein 3alpha), and conditioned media were assessed for matrix-degrading enzyme contents (matrix metalloproteinases [MMPs] 1, 3, and 13, and N-acetyl-beta-D-glucosaminidase [NAG]). Cell proliferation and phenotype modulation were evaluated by bromodeoxyuridine incorporation and cathepsin B production. Induction of cell proliferation was assessed in cartilage explants by immunodetection of the proliferation-associated antigen S100A4. RESULTS: CXCR3, CXCR4, CXCR5, and CCR6 were detected on human chondrocytes. CXCR3 and CXCR4 expression was increased in exponentially growing chondrocyte subcultures. Ligands of all receptors enhanced the release of MMPs 1, 3, and 13. Release of NAG and cathepsin B was significantly higher in chemokine-stimulated cultures than in unstimulated cultures. SDF-1alpha and BCA-1 also induced DNA synthesis and chondrocyte proliferation, as was shown by the up-regulation of S100A4 in cartilage explants as well. CONCLUSION: Our findings extend the repertoire of functional responses elicited by the activity of chemokines on chondrocytes and open new avenues in our understanding of the control of chondrocyte differentiation status by chemokines and their receptors.

Acetylglucosaminidase↗

PubMed2003

Phenotypic modulation of smooth muscle cells and vascular remodeling in intraparenchymal small cerebral arteries after canine experimental subarachnoid hemorrhage.

Cerebral microcirculatory changes are an important factor regulating cerebral blood flow. The aim of this study was to investigate the possibility of phenotypic modulation of smooth muscle cell (SMC) and vascular remodeling of intraparenchymal small cerebral arteries after subarachnoid hemorrhage (SAH). Seven to 14 days after canine experimental SAH, in intraparenchymal perforating arteries, the amount of beta-actin mRNA evaluated by Northern blot analysis increased, the structural change of the 3' untranslated region of beta-actin mRNA detected by polymerase chain reaction analysis was enhanced, and immunohistochemistry showed marked induction of the embryonal isoform of myosine heavy chain accompanied by decreased expression of smooth muscle myosin heavy chain (SM2). Histological morphometric analysis showed an increase in the area of the arterial wall without changes in the number of nuclei of SMC. This is the first report suggesting that vascular remodeling accompanied by phenotypic modulation occurs in intraparenchymal small arteries. These changes may affect cerebral blood flow after SAH by inducing increased cerebrovascular resistance.

Actins↗

PubMedDate not supplied

Caldesmon isoform associated with phenotypic modulation of mesangial cells.

Caldesmon (CaD) is a major calmodulin- and actin-binding protein distributed in smooth muscle cells (SMC) and nonmuscle cells. There are at least two high-molecular-weight CaD (h-CaD) isoforms and four low-molecular-weight CaD (l-CaD) isoforms produced by alternative splicing. Isoformal interconversion is associated with phenotypic modulations of vascular SMC. We investigated the CaD isoform in human and rat glomerular mesangial cells (MC) to characterize the phenotypic changes of MC involved in glomerular diseases. A Western blot analysis and reverse-transcription analysis using exon-specific primers revealed that one l-CaD isoform lacking exons 1, 3b and 4 was predominantly expressed in human cultured MC. The expression of this isoform was markedly enhanced in anti-Thy1.1 nephritis rats and streptozotocin-induced diabetic rats, while little expression was observed in the normal glomerulus. Isoformal interconversion did not occur during the phenotypic changes of MC. These data suggested that the activated MC resembled dedifferentiated SMC in terms of the CaD expression pattern, and that CaD is a useful marker of the phenotypic modulations of MC.

Animals↗

PubMed2002

Exercise training attenuates coronary smooth muscle phenotypic modulation and nuclear Ca2+ signaling.

Physical inactivity is an independent risk factor for coronary heart disease, yet the mechanism(s) of exercise-related cardioprotection remains unknown. We tested the hypothesis that coronary smooth muscle after exercise training would have decreased mitogen-induced phenotypic modulation and enhanced regulation of nuclear Ca(2+). Yucatan swine were endurance exercise trained (EX) on a treadmill for 16-20 wk. EX reduced endothelin-1-induced DNA content by 40% compared with sedentary (SED) swine (P < 0.01). EX decreased single cell peak endothelin-1-induced cytosolic Ca(2+) responses compared with SED by 16% and peak nuclear Ca(2+) responses by 33% (P < 0.05), as determined by confocal microscopy. On the basis of these results, we hypothesized that sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and intracellular Ca(2+) stores in native smooth muscle are spatially localized to dissociate cytosolic Ca(2+) and nuclear Ca(2+). Subcellular localization of SERCA in living and fixed cells revealed a distribution of SERCA near the sarcolemma and on the nuclear envelope. These results show that EX enhances nuclear Ca(2+) regulation, possibly via SERCA, which may be one mechanism by which coronary smooth muscle cells from EX are less responsive to mitogen-induced phenotypic modulation.

Animals↗