SEARCH · PubMed Health

Results for “Phenotypic modulation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources

PubMed1987

Cellular senescence revisited: a review.

The field of cellular senescence (cytogerontology) is reviewed. The historical precedence for investigation in this field is summarized, and placed in the context of more recent studies of the regulation of cellular proliferation and differentiation. The now-classical embryonic lung fibroblast model is compared to models utilizing other cell types as well as cells from donors of different ages and phenotypes. Modulation of cellular senescence by growth factors, hormones, and genetic manipulation is contrasted, but newer studies in oncogene involvement are omitted. A current consensus would include the view that the life span of normal diploid cells in culture is limited, is under genetic control, and is capable of being modified. Finally, embryonic cells aging in vitro share certain characteristics with early passage cells derived from donors of increasing age.

Aging↗

PubMed1988

Role of protein kinase C in the control of vascular prostacyclin: study of phorbol esters effect in bovine aortic endothelium and smooth muscle.

In bovine aortic endothelial cells, phorbol 12-myristate, 13-acetate induced a smaller stimulation of prostacyclin release than ionophore A23187: the combination of both agents was highly synergistic. The responses of the bovine aortic smooth muscle were very different in the 2 preparations studied. In media explants cultured for short periods, neither phorbol 12-myristate, 13-acetate, nor A23187, alone or in combination, were able to increase prostacyclin release, whereas serotonin was an effective stimulus. In cultured smooth muscle cells, outgrown from the explants, phorbol 12-myristate, 13-acetate increased prostacyclin release to the same levels as A23187 or serotonin. It is concluded that increased cytosolic Ca++ level and protein kinase C activity induce a synergistic stimulation of endothelial prostacyclin. On the other hand, the phenotypic modulation of the arterial smooth muscle, from a contractile to a synthetic state, seems to be associated with a profound change in the control of prostacyclin.

Animals↗

PubMed1992

Proliferative responses of quail aortic smooth muscle cells to benzo[a]pyrene: implications in PAH-induced atherogenesis.

Repeated exposure of avian and rodent species to benzo(a)pyrene (BaP) has been associated with the development of aortic lesions of atherosclerotic etiology. Because the occurrence of these lesions may involve alterations in the regulation of smooth muscle cell (SMC) growth, the present studies were conducted to evaluate the proliferative responses of quail aortic SMCs to BaP treatment in vivo and in vitro. Measurements of [3H]thymidine incorporation and cell growth were conducted in cultured aortic SMCs isolated from male Japanese quail treated with 10 mg/kg BaP or vehicle weekly for 10 weeks or in naive aortic SMCs exposed in vitro to BaP (0.003-30 microM). Inhibition of DNA synthesis was observed in primary and early passage cultures of aortic SMCs isolated from BaP-treated quail relative to controls. Continued propagation of these cultures yielded a population of BaP cells which proliferated at faster rates than controls. The proliferative phenotype induced by BaP was first observed after the tenth passage and preserved in all subsequent passages tested. In vitro growth of SMCs from BaP-treated animals was serum- and anchorage-dependent. A 24-h exposure of cycling SMC cultures to BaP (0.003-30 microM) was associated with a dose-dependent decrease in DNA synthesis and significant delay in the progression of SMCs through the cell cycle. A time-course study revealed that maximal inhibition of DNA synthesis occurred 10 h after addition of 3 microM BaP to cycling cultures of SMCs. As seen in SMCs isolated from BaP-treated quail, serial subculture of SMCs exposed to 0.3 microM BaP in vitro for 24 h yielded a fast-growing population of cells. In these cultures, expression of the proliferative phenotype was observed after the fifth passage. These data suggest that BaP induces the expression of a proliferative phenotype in aortic SMCs characterized by enhanced serum responsiveness. This phenotypic modulation may contribute to the initiation and/or progression of vascular lesions of atherosclerotic etiology induced by BaP.

Animals↗

PubMed1994

Induction of non-responsiveness in human allergen-specific type 2 T helper cells.

Activation of allergen-reactive human T helper (Th)2 cells in the absence of professional antigen-presenting cells, induces non-responsiveness or anergy in these cells in vitro. This induction of anergy is accompanied by phenotypic modulation and altered cytokine production. Furthermore, peptide-treated Th2 cells fail to provide B-cell help for IgE synthesis. Recent studies indicate that impaired signal transduction via the T-cell receptor may account for the lack of responsiveness to antigenic stimulation. Here, we review present knowledge on the cell biology of non-responsive or anergic Th2 cells.

Allergens↗

PubMed1992

Osteogenic phase-specific co-regulation of collagen synthesis and mineralization by beta-glycerophosphate in chick periosteal cultures.

Mineralized bone formation in vitro can be induced by the alkaline phosphatase substrate beta-glycerophosphate (GP). GP may not only be essential for mineralization in vitro, but could also modulate other metabolic activities of bone cells, particularly if GP is presented to these cells during different phases of development. To assess GP modulation of bone cell metabolism, biochemical and autoradiographic analyses of chick periosteal cultures treated with GP were performed. About 50% less (p less than 0.05) Type I collagen was produced in periosteal cultures treated with GP. If the fibrous portion of the periostem was microdissected from the osteogenic layer prior to culture, GP inhibition of Type I collagen synthesis was even more marked (60%: p less than 0.05). To define organic phosphate-sensitive phases of osteogenesis, cultures were exposed to GP for various time periods. Mineralization occurred reproducibly when periosteal cultures were treated with GP from the outset of the incubation period (positive control). However, if GP was added after the third day of incubation, phosphate content was the same as in positive control cultures, whereas calcium content was significantly (20%: p less than 0.05) lower. Moreover, if GP was added on day 6, there was virtually no calcium accumulation by day 12, while massive amounts of phosphate had accumulated. Taken together, these findings indicate that organic phosphates may modulate phenotypic expression of osteogenic cells, and that osteogenic cells traverse an organic phosphate-sensitive phase, after which they may be incapable of normal mineralization.

Animals↗

PubMed2006

Redox signalling in vascular responses to shear and stretch.

Blood vessels are permanently exposed to stretch and shear stress due to blood pressure and blood flow. Significant variations in the mechanical environment, of physiological or pathophysiological nature, occur in vivo. These trigger acute changes in vessel diameter that tend to restore basal levels of tensile and shear stress. However, when altered mechanical conditions persist, they lead to compensatory phenotypical modulation of the endothelial and vascular smooth muscle cells, producing structural and functional modifications of the arterial wall. Such vascular remodelling is a fundamental basis of normal vessel growth and adaptation. However, when the vascular environment changes, due to humoral, metabolic or surgical alterations, for example, mechanical factors may actually exacerbate the underlying conditions and contribute significantly to disease progression. Several studies have demonstrated that reactive oxygen species are induced in the vascular response to changes in shear stress or stretch. It appears that the balance between oxidant and antioxidant generation, which is directly determined by the nature of the mechanical stimulus, can greatly influence the process of vascular remodelling, contributing to both transient and more prolonged adaptations.

Animals↗

PubMed2004

Exaggerated production of nitric oxide (NO) and increases in inducible NO-synthase mRNA levels induced by the pro-inflammatory cytokine interleukin-1beta in vascular smooth muscle cells of elderly rats.

Nitric oxide (NO) is produced at high levels by inducible nitric oxide synthase (iNOS) during inflammation and other pathological conditions, contributing to development of cardiovascular diseases. The present study determined if aging affects the ability of interleukin-1beta (IL-1beta), a pro-inflammatory cytokine, to induce increased NO production (assessed by Griess reaction) and iNOS mRNA levels (assessed by RT-PCR/agarose gel electrophoresis) in vascular smooth muscle cells (VSMCs) from young (3-month-old) and elderly (20-22-month-old) rats. The VSMCs cells were used only in early passages (passages 0 and 1) to avoid phenotypic modulation. To uncover subtle differences in basal iNOS mRNA levels in VSMCs of young and elderly rats, RT-PCR products were also analyzed by a new ultrasensitive technique using capillary electrophoresis with laser-induced fluorescence detector (CE-LIF). IL-1beta (5 ng/ml) significantly (P < 0.05) increased NO production 3.7-fold in elderly female VSMCs and 6.7-fold in elderly male VSMCs, but had no detectable effect in young female and male VSMCs. Basal iNOS mRNA levels (assessed by RT-PCR/CE-LIF) were dramatically higher in VSMCs of elderly male rats compared to young ones. In general, VSMCs of elderly rats showed much greater sensitively to iNOS-inducing actions of IL-1beta. These data give new insight into effects of aging on iNOS expression in VSMCs, showing dramatic increases in both basal and stimulated iNOS mRNA levels, which may contribute to the development of vascular diseases in the elderly.

Animals↗

PubMed2004

Copper-induced hepatotoxicosis with hepatic stellate cell activation and severe fibrosis in North Ronaldsay lambs: a model for non-Wilsonian hepatic copper toxicosis of infants.

Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.

Animals↗

PubMed2004

Histological observation of complete closure of anterior capsulotomy in 2 cases.

We report the histological finding of complete closure of the anterior capsulotomy window in 2 cases. The cases were successfully treated with surgery after neodymium:YAG laser anterior capsulotomy failed. Histology and immunohistochemistry were performed to determine the pathogenesis. Histology revealed the presence of elongated, fibroblast-like lens epithelial cells in association with extracellular matrix accumulation, which were positive for collagen types, fibronectin, and osteopontin. The cells were labeled with anti-alpha-smooth muscle actin antibody. The finding indicates that phenotypic modulation in lens epithelial cell to contractile cell type and accumulation of matrix are involved in closure of the anterior capsulotomy window.

Aged↗

PubMed2004

Aging blunts remodeling of the uterine artery during murine pregnancy.

OBJECTIVE: The progressive increase in uterine blood flow (UBF) during pregnancy is accommodated by morphologic changes in the uterine artery (UA) in a process defined as arterial remodeling. This process is accompanied by changes in cytoskeletal architecture of the arterial smooth muscle cells (SMCs) and surrounding extracellular matrix (ECM). Aging reduces flow-induced arterial remodeling. We studied changes in the murine UA during pregnancy and on the effects of aging on the capacity of the UA to remodel in response to pregnancy. METHODS: We determined morphologic and cytologic changes in UA from nonpregnant and pregnant mice aged 12 weeks (young) and 40 weeks (old) and correlated them with their reproductive performance. RESULTS: In young mice, pregnancy induced an early increase in UA wall mass, which preceded lumen widening. These changes were not accompanied by altered densities of elastin and collagen in the ECM of the medial layer. Smooth muscle cell proliferation increased in midpregnancy and was paralleled by a transient decrease in smoothelin and smooth muscle alpha-actin expression. In old mice, these pregnancy-dependent changes in the UA wall were either absent or markedly reduced. Although by day 11 of pregnancy litter size did not differ between both age groups, the number of viable pups in old mice by day 17 of pregnancy and at birth was 25% and 60% less than in young mice. CONCLUSION: Outward hypertrophic remodeling of the UA during pregnancy in young mice is characterized by transient phenotypic modulation and proliferation of SMCs and alterations in the composition of the ECM. In contrast, in older mice, UA remodeling is markedly reduced and accompanied with a loss of viable fetuses near term pregnancy.

Aging↗

PubMed2004

Microscale tissue engineering using gravity-enforced cell assembly.

Designing artificial microtissues by reaggregation of monodispersed primary cells, neoplastic or engineered cell lines is providing insight into cell-cell interactions and underlying regulatory networks. Recent advances in microtissue production have highlighted the potential of scaffold-free cell aggregates in maintaining tissue-specific functionality, supporting seamless integration of implants into host tissues, and providing complex feeder structures for difficult-to-differentiate cell types. Furthermore, these tissues are amenable to therapeutic and phenotype-modulating interventions using latest-generation transduction technologies. Microtissues produce therapeutic transgenes at increased levels and offer tissue-like assay environments to improve drug-function correlations in current discovery programs. Here, we outline scaffold-free microtissue design in liver, heart and cartilage, and discuss how this technology could significantly impact regenerative medicine.

Animals↗

PubMed2004

MIBG, an inhibitor of arginine-dependent mono(ADP-ribosyl)ation, prevents differentiation of L6 skeletal myoblasts by inhibiting expression of myogenin and p21(cip1).

The development of skeletal muscle is controlled by a highly synchronized series of cellular events, and various signals from both inside and outside the cell play a role in the switch from multipotential mesodermal stem cells to muscle fibers. Meta-iodobenzylguanidine (MIBG), an inhibitor of mono(ADP-ribosyl)ation, has been shown to prevent terminal differentiation of skeletal myoblasts; however, its mechanism of action has not been established. We recently reported that MIBG is capable of preventing phenotypic modulation of smooth muscle cells by interfering with specific trans-acting factors [L. Yau, B. Litchie, S. Thomas, B. Storie, N. Yurkova, P. Zahradka, Endogenous mono-ADP-ribosylation mediates smooth muscle cell proliferation and migration via protein kinase N-dependent induction of c-fos expression. Eur. J. Biochem. 270 (2003) 101-110.]. We therefore examined the effect of MIBG on select myogenic regulatory factors known to control terminal differentiation. It was confirmed that MIBG, but not inhibitors of poly-ADP-ribose polymerase (3-aminobenzamide, PD128763), inhibits fusion of L6 skeletal myoblasts in a concentration-dependent manner. Moreover, inhibition by MIBG correlated with a failure to induce expression of myogenin and p21(cip1), while levels of MyoD and MEF2 were unaffected. Time-of-addition studies revealed that MIBG also affected a late event possibly linked to cell fusion. Finally, arginine-dependent mono(ADP-ribosyl)transferase activity increased over the first 24 h of the differentiation period. These data support a role for arginine-dependent mono(ADP-ribosyl)transferase as an essential positive regulator of differentiation in skeletal muscle cells that operates by modulating the expression of specific myogenic factors.

3-Iodobenzylguanidine↗

PubMed2002

Lipoprotein(a) promotes smooth muscle cell proliferation and dedifferentiation in atherosclerotic lesions of human apo(a) transgenic rabbits.

Elevated plasma lipoprotein(a) [Lp(a)] levels constitute an independent risk factor for the development of atherosclerosis. However, the mechanism underlying Lp(a) atherogenicity is unclear. Recently, we demonstrated that Lp(a) may potentially be proatherogenic in transgenic rabbits expressing human apolipoprotein(a) [apo(a)]. In this study, we further investigated atherosclerotic lesions of transgenic rabbits by morphometry and immunohistochemistry. On a cholesterol diet, human apo(a) transgenic rabbits had more extensive atherosclerotic lesions of the aorta, carotid artery, iliac artery, and coronary artery than did nontransgenic littermate rabbits as defined by increased intimal lesion area. Enhanced lesion development in transgenic rabbits was characterized by increased accumulation of smooth muscle cells, that was often associated with the Lp(a) deposition. To explore the possibility that Lp(a) may be involved in the smooth-muscle cell phenotypic modulation, we stained the lesions using a panel of monoclonal antibodies against smooth-muscle myosin heavy-chain isoforms (SM1, SM2, and SMemb) and basic transcriptional element binding protein-2 (BTEB2). We found that a large number of smooth muscle cells located in the apo(a)-containing areas of transgenic rabbits were positive for SMemb and BTEB2, suggesting that these smooth muscle cells were either immature or in the state of activation. In addition, transgenic rabbits showed delayed fibrinolytic activity accompanied by increased plasma plasminogen activator inhibitor-1. We conclude that Lp(a) may enhance the lesion development by mediating smooth muscle cell proliferation and dedifferentiation possibly because of impaired fibrinolytic activity.

Animals↗

PubMed2000

Differential expression of proteoglycans biglycan and decorin during neointima formation after stent implantation in normal and atherosclerotic rabbit aortas.

Proteoglycans decorin and biglycan, which bind to TGF-beta, are thought to participate in regulation of extracellular matrix accumulation in arterial intimal hyperplasia. To investigate the correlation of these proteoglycans with the cellular localization and phenotypic modulation of smooth muscle cells (SMCs), we analyzed the spatial and chronological distribution of these proteoglycans and two cytokines, TGF-beta and IL-1beta, in the process of neointima formation after stent implantation in the aortas of rabbits fed a high-cholesterol diet (atherosclerotic group) or a regular diet (control group). We implanted metallic stents in the rabbit aortas and harvested the aortas 4-56 days later for immunohistochemical and mRNA in situ hybridization analyses. In the control group, TGF-beta and biglycan expression was in correspondence with the chronology and localization of embryonic SMCs. In the atherosclerotic group, TGF-beta and biglycan expression was sustained throughout the experimental period, which was in accord with the prolonged expression of embryonic SMCs. Decorin, which did not occur in neointima in the control group, appeared in the atherosclerotic aortas in the confined area of vascular SMCs surrounding the macrophages around the stent wire. These results indicate that biglycan and decorin kinetics during neointima formation after arterial injury are distinct, despite their similar construction; biglycan synthesis correlates with embryonic SMCs.

Animals↗

PubMed2000

Inducible expression of basic transcription element-binding protein 2 in proliferating smooth muscle cells at the vascular anastomotic stricture.

OBJECTIVE: The proliferation of vascular smooth muscle cells surrounding a suture line is an important factor in the development of anastomotic stricture that is frequently seen after coronary artery bypass grafting. The aim of this study was to investigate the time course of intimal thickening and to examine the expression of the molecular marker of smooth muscle cell activation surrounding the suture line. METHODS: Longitudinal aortotomy was performed in the abdominal aorta of rats. The rats were put to death 1, 2, 4, and 8 weeks after aortotomy, and the percentage of the lumen occluded by intimal thickening was calculated. All tissues were stained with antibodies against basic transcription element- binding protein 2, human cyclin-dependent kinase (cdk4), and Sp1 for immunohistochemistry. Basic transcription element-binding protein 2 is a transcription factor that is involved in phenotypic modulation of vascular smooth muscle cells. Cdk4 represents a marker for G(1) phase of the cell cycle. Sp1 is a transcription factor known to be expressed in a variety of tissues. Basic transcription element-binding protein 2 messenger RNA expression was confirmed by means of reverse transcriptase-polymerase chain reaction. RESULTS: We noted significant thickening of the intimal layer 1 week after aortotomy. Immunohistochemistry demonstrated that smooth muscle cells in the neointima were strongly positive for basic transcription element-binding protein 2 and human cyclin-dependent kinase 4, which peaked 2 weeks after aortotomy. Basic transcription element-binding protein 2 expression was closely associated with human cyclin-dependent kinase 4 expression in the neointima, although Sp1 was not. Basic transcription element-binding protein 2 messenger RNA levels were significantly up-regulated early after aortotomy. CONCLUSION: The experimental rat aortotomy model is useful to investigate the proliferation of vascular smooth muscle cells around the suture line. Moreover, our results suggest the possible role of basic transcription element-binding protein 2 in the development of vascular anastomotic strictures.

Anastomosis, Surgical↗

PubMed1997

Muscle-specific actin expression in chondroblastomas.

Chondroblastomas are unusual cartilage benign lesions of bone that have well-characterized histological features. We reviewed and immunohistochemically examined the paraffin block material of 20 cases, and in seven tumors of this collection we found distinct cytoplasmic muscle-specific actin positivity of some tumor chondroblasts and chondrocytes. Muscle-specific actin-positive cells had the histological and ultrastructural features typical of chondroblasts. Moreover, in their cytoplasm they contained bundles of microfilaments with focal densities, as is typical of myofilaments. We did not observe any basal lamina around these cells, which were surrounded by intercellular matrix of the cartilage tissue type. Therefore, we suppose that muscle-specific actin-positive cells occurring in some chondroblastomas do not represent an admixture of myofibroblasts but chondroblasts with actin expression. The unusual immunophenotype of some chondroblasts might be the result of aberrant actin expression or of the plasticity of their phenotype modulated by microenvironmental stimuli. It is a question of whether, analogously to the terminology of myofibroblasts, such cells could be designated as myochondroblasts.

Actins↗

PubMed1995

Scatter factor and angiogenesis.

Scatter factor (hepatocyte growth factor) is a mesenchyme-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. These responses are transduced through the c-met protooncogene product, a transmembrane tyrosine kinase that functions as the SF receptor. SF is a potent angiogenic molecule, and its angiogenic activity is mediated primarily through direct actions on endothelial cells. These include stimulation of cell motility, proliferation, protease production, invasion, and organization into capillary-like tubes. SF is chronically overexpressed in tumors, suggesting that it may function as a tumor angiogenesis factor. SF production in tumors may be due, in part, to an abnormal tumor-stroma interaction, in which the tumor cells secrete factors (SF-IFs) that stimulate SF production by tumor-associated stromal cells. Studies suggest a link between tumor suppressors (antioncogenes) and inhibition of angiogenesis. We hypothesize that tumor suppressor gene mutations may contribute to the activation of an SF-IF-->SF-->c-met pathway, leading to an invasive and angiogenic tumor phenotype. Modulation of this pathway may, ultimately, provide clinically useful methods of enhancing or inhibiting angiogenesis.

Animals↗

PubMed2000

The multiple actions of angiotensin II in atherosclerosis.

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system, has been implied in the pathogenesis of atherosclerosis on various levels. There is abundant experimental evidence that pharmacological antagonism of Ang II formation by angiotensin converting enzyme inhibition or blockade of the cellular effects of Ang II by angiotensin type 1 receptor blockade inhibits formation and progression of atherosclerotic lesions. Angiotensin promotes generation of oxidative stress in the vasculature, which appears to be a key mediator of Ang II-induced endothelial dysfunction, endothelial cell apoptosis, and lipoprotein peroxidation. Ang II also induces cellular adhesion molecules, chemotactic and proinflammatory cytokines, all of which participate in the induction of an inflammatory response in the vessel wall. In addition, Ang II triggers responses in vascular smooth muscle cells that lead to proliferation, migration, and a phenotypic modulation resulting in production of growth factors and extracellular matrix. While all of these effects contribute to neointima formation and development of atherosclerotic lesions, Ang II may also be involved in acute complications of atherosclerosis by promoting plaque rupture and a hyperthrombotic state. Accordingly, Ang II appears to have a central role in the pathophysiology of atherosclerosis.

Angiotensin II↗