PubMed Health⌕ Search

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 109 records · Page 6Linked to original sources
PubMed2005

Phenotypic modulation of intima and media smooth muscle cells in fatal cases of coronary artery lesion.

OBJECTIVE: Characterize the phenotypic features of media and intima coronary artery smooth muscle cells (SMCs) in mildly stenotic plaques, erosions, stable plaques, and in-stent restenosis. METHODS AND RESULTS: Expression of alpha-smooth muscle actin (alpha-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin was investigated by immunohistochemistry followed by morphometric quantification. The cross-sectional area and the expression of cytoskeletal proteins in the media were lower in restenotic lesions and, to a lesser extent, in stable plaques compared with mildly stenotic plaques and erosions. An important expression of alpha-SMA was detected in the intima of the different lesions; moreover, alpha-SMA staining was significantly larger in erosions compared with all other conditions. In the same location, a striking decrease of SMMHCs and a disappearance of smoothelin were observed in all situations. CONCLUSIONS: Medial atrophy is prevalent in restenotic lesions and stable plaques compared with mildly stenotic plaques and erosions. Intimal SMCs of all situations exhibit a phenotypic profile, suggesting that they have modulated into myofibroblasts (MFs). The high accumulation of alpha-SMA-positive MFs in erosions compared with stable plaques correlates with the higher appearance of thrombotic complications in this situation.

Actins↗
PubMed1985

Mouse phenotype modulates the behavioral effects of acute thiamine deficiency.

The influence of mouse phenotype on the behavioral effects of thiamine deficiency was examined in three experiments. A reduction in spontaneous motor activity occurring during acute thiamine deprivation was found to be greater in C57 mice than in Balb and Nylar mice. No persistent post-deprivation effects were observed nor were there any changes in Y-maze alternation or spatial discrimination learning. These results provide a further demonstration of genetic-environmental interactions in determining pathological behavioral states.

Acute Disease↗
PubMed2003

Thrombin and phenotypic modulation of the endothelium.

Thrombin signaling in the endothelium is linked to multiple phenotypic changes, including alterations in permeability, vasomotor tone, and leukocyte trafficking. The thrombin signal is transduced, at least in part, at the level of gene transcription. In this review, we focus on the role of thrombin signaling and transcriptional networks in mediating downstream gene expression and endothelial phenotype. In addition, we report the results of DNA microarrays in control and thrombin-treated endothelial cells. We conclude that (1) thrombin induces the upregulation and downregulation of multiple genes in the endothelium, (2) thrombin-mediated gene expression involves a multitude of transcription factors, and (3) future breakthroughs in the field will depend on a better understanding of the spatial and temporal dynamics of these transcriptional networks.

Blood Coagulation↗
PubMed1991

A standardised method of culturing aortic explants, suitable for the study of factors affecting the phenotypic modulation, migration and proliferation of aortic smooth muscle cells.

The study of factors affecting phenotypic change and growth of aortic smooth muscle cells (SMC) typically involves either the isolation of SMC by enzymatic dissociation or observation of outgrowth of cells from primary explants of vascular tissue. Explants provide a system in which the growth of cells can be investigated without dissociating them totally from their normal environment and avoids some of the problems of variability associated with enzymatic digestion. We describe here a standardised method for the preparation of medial explants of arterial tissue using a McIlwain tissue chopper, which is both fast and reproducible. Measurement was made of the percentage of explants showing outgrowth and of the distance migrated by cells at various times after plating explants singly into wells of a 96-well plate. Using this method, by 12 days after explanting, more than 95% of explants from normal rabbit aorta had shown outgrowth, in contrast to only 50% of explants prepared using a scalpel blade. Explants from atherosclerotic rabbit aorta showed a shorter lag phase before outgrowth commenced than explants from normal rabbit aorta of a similar age, but the subsequent rate of growth was the same. In contrast, when explants of normal rabbit aorta were grown in hyperlipidic rabbit serum, the lag phase was the same as for normal serum, but the subsequent rate of growth was greater. Explants from normal rabbit aorta treated with heparin showed an increased lag phase but reduced rate of growth. Treatment with heparinase decreased the lag phase and increased the rate of growth as did elastase.

Animals↗
PubMed2003

Phenotypic modulation of the stromal reticular network in normal and neoplastic lymph nodes: tissue transglutaminase reveals coordinate regulation of multiple cell types.

The lymph node paracortex is composed of a network of fibroblastic reticular cells (FRC) and reticular fibers linking sinuses to blood vessels. Using immunostaining for the inducible enzyme/adhesion molecule tissue transglutaminase (TG), we demonstrate coordinate regulation of multiple stromal cell types of this reticular network including FRC, endothelial cells and sinus lining cells. Tissue transglutaminase is expressed at low levels in the paracortex around primary follicles but is markedly up-regulated in stromal cells around hyperplastic germinal centers and then down-regulated around regressing follicles. In cultured FRC, TG is induced 5- to 20-fold and becomes colocalized with matrix proteins by treatment with interleukin-4, but not by other cytokines that are commonly increased in lymph upon immune activation. Coordinate TG up-regulation is observed surrounding nodules of follicular lymphoma (14 of 15 cases) and in the FRC and endothelium of classical Hodgkin's disease, two tumor types that also showed an activated paracortical phenotype. Small lymphocytic lymphoma showed minimal TG staining, with other lymphoma types showing patterns suggesting differential TG regulation. Using TG as a stromal marker, we have identified differential modulation of the phenotype of the lymph node reticular network that parallels change in the B-cell compartment.

Animals↗
PubMed2003

Phenotype modulation in vascular tissue engineering using biochemical and mechanical stimulation.

Biochemical stimulation was applied in combination with cyclic mechanical strain to engineered vascular constructs made of isolated smooth muscle cells in a three-dimensional (3D) collagen type 1 matrix. Platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta) were added exogenously to the medium used to culture the constructs. Mechanical stimulation was applied using a bioreactor system that imparted a 10% circumferential strain at a frequency of 1 Hz. The parameters studied were gel compaction, cell proliferation, and expression of the contractile protein smooth muscle alpha-actin (SMA). Mechanical stimulation caused a characteristic increase in gel compaction and cell proliferation, relative to statically cultured controls. Stimulation with PDGF increased cell proliferation and decreased SMA expression in 3D gels, but inhibited the effects of mechanical stimulation and produced a more open matrix structure. TGF-beta strongly inhibited cell proliferation and increased SMA expression, especially in the presence of mechanical strain, and resulted in a dense matrix. These results show that cell phenotype can be modulated in engineered blood vessels by applying selected combinations of biochemical and mechanical stimuli, and suggest that such control over cell function can be used to tailor the properties of engineered tissues.

Actins↗
PubMed2005

Inhibition of cGMP-dependent protein kinase reverses phenotypic modulation of vascular smooth muscle cells.

We have previously shown that type I cGMP-dependent protein kinase (PKG) can alter the phenotype of cultured vascular smooth muscle cells (VSMCs). Although the expression of contractile proteins in VSMCs has been shown to be modulated with the induction of PKG, experiments in which PKG inhibition brings about reduced expression of contractile markers have not been performed. To more thoroughly examine the role of PKG in the expression of contractile proteins, recombinant adenovirus containing the PKG coding sequence (AD-PKG) was used to induce gene expression and morphologic changes in adult rat aortic VSMCs. Cells expressing PKG, but not control adenovirus-infected cells, began to express a specific marker protein for the contractile phenotype, smooth muscle myosin heavy chain (SMMHC), within 48 hours of PKG induction. The morphology of the AD-PKG-infected cells began to change from a fibroblastic phenotype to a spindle-shaped phenotype within 72 hours after PKG induction. The specific cell-permeable PKG inhibitory peptide DT-2, but not control peptides, reversed the biochemical and morphologic changes associated with PKG expression. These results suggest that PKG expression and activity in cultured VSMCs is capable of altering the VSMC phenotype. These data also verify the intracellular action of DT-2 and reveal uptake and dynamic properties of this PKG-inhibiting peptide.

Adenoviridae↗
PubMed1998

Phenotypic modulation of smooth muscle cells during formation of neointimal thickenings following vascular injury.

Smooth muscle cells build up the media of mammalian arteries and constitute one of the principal cell types in atherosclerotic and restenotic lesions. Accordingly, they show a high degree of plasticity and are able to shift from a differentiated, contractile phenotype to a less differentiated, synthetic phenotype, and then back again. This modulation occurs as a response to vascular injury and includes a prominent structural reorganization with loss of myofilaments and formation of an extensive endoplasmic reticulum and a large Golgi complex. At the same time, the expression of cytoskeletal proteins and other gene products is altered. As a result, the cells lose their contractility and become able to migrate from the media to the intima, proliferate, and secrete extracellular matrix components, thereby contributing to the formation of intimal thickenings. The mechanisms behind this change in morphology and function of the smooth muscle cells are still incompletely understood. A crucial role has been ascribed to basement membrane proteins such as laminin and collagen type IV and adhesive proteins such as fibronectin. A significant role is also played by mitogenic proteins such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). An improved knowledge of the regulation of smooth muscle differentiated properties represents an important part in the search for new methods of prevention and treatment of vascular disease.

Angioplasty↗
PubMed1984

Phenotypic modulation of chronic lymphocytic leukemia cells by phorbol ester: induction of IgM secretion and changes in the expression of B cell-associated surface antigens.

Freshly explanted neoplastic populations from 22 cases of phenotypically well-characterized chronic type B lymphocytic leukemia were studied for their capacity to respond to the phorbol ester TPA in vitro. In all but four cases the secretion of IgM was either induced or increased, often to a high level. In contrast, the export of free immunoglobulin (Ig) light chains, an almost consistent feature of the B lymphocytic leukemias, remained relatively constant after TPA treatment. Parallel changes in leukemic cell surface phenotype were probed with both "conventional" and monoclonal antibodies, revealing some modulation of markers in every case investigated. A diminution in the level of surface Ig (preferentially IgD) and the accumulation of cytoplasmic Ig observed after phorbol ester treatment were accompanied by a corresponding reduction or loss of the B1 antigen and usually of B2 when present. The most consistent change induced by TPA was the appearance of BB-1, a marker of activated B lymphocytes, which was rarely expressed on fresh leukemic cells. Another marker of activated lymphocytes, LB-1, was also often induced or increased in its expression after exposure of the cells to TPA. The magnitude of the TPA response appeared to relate to the stage of maturation arrest of the individual leukemic clones rather than to any clinical parameter explored. The significance of the findings to normal B cell differentiation and their potential clinical utility are discussed.

Antigens, Neoplasm↗
PubMed1984

Phenotype modulation in primary cultures of arterial smooth-muscle cells. Dual effect of prostaglandin E1.

The effects of prostaglandin E1 (PGE1) on the phenotypic state of enzymatically isolated arterial smooth-muscle cells in primary culture were studied by transmission electron microscopy, thymidine autoradiography, and cell counting. Early in culture (day 0-2), PGE1 stimulated conversion of the cells from contractile (less euchromatic nucleus and cytoplasm dominated by myofilament bundles) to synthetic state (more euchromatic nucleus and cytoplasm dominated by cisternae of rough endoplasmic reticulum and a large Golgi complex). The rate of entrance of the cells into DNA synthesis and mitosis was also increased at this time. Later on (day 3-6), when the majority of the cells had entered synthetic state, PGE1 inhibited DNA synthesis and cellular proliferation. These observations indicate that the effect of prostaglandins on arterial smooth muscle is dual in nature and dependent on the state of differentiation of the cells.

Alprostadil↗
PubMed1986

Phenotype modulation in primary cultures of smooth-muscle cells from rat aorta. Synthesis of collagen and elastin.

Early in primary culture, arterial smooth-muscle cells undergo a transition from a contractile to a synthetic phenotype. This process includes the loss of myofilaments and of contractility. At the same time, an extensive rough endoplasmic reticulum and a large Golgi complex are formed, and active synthesis of DNA, RNA and proteins commences. In the present study, chemical and immunocytochemical methods were used to investigate the production of extracellular-matrix proteins in relation to this change in phenotypic properties. The results showed that the phase of rapid cellular proliferation that follows the structural modulation of smooth-muscle cells is associated with high rates of collagen and elastin synthesis, as measured by the incorporation of 3H-proline into 3H-hydroxyproline and 3H-valylproline, respectively. SDS-polyacrylamide gel electrophoresis and fluorography indicated that type-I collagen is the main collagen species synthesized by these cells. Smaller amounts of type-V collagen and (although not definitively identified) type-III collagen were also detected. Indirect immunofluorescence and immunoelectron microscopy demonstrated that smooth-muscle cells surround themselves with an incomplete basement membrane, containing laminin and type-IV collagen, and thin fibrils of type-I collagen. Adjacent to these fibrils, aggregates of amorphous, elastin-like material were also found. Our observations confirm and extend earlier notions of a close similarity between the behaviour of arterial smooth-muscle cells during in vitro cultivation and during the early stages of the formation of atherosclerotic lesions.

Animals↗
PubMed1998

Nitric oxide--cyclic GMP pathway regulates vascular smooth muscle cell phenotypic modulation: implications in vascular diseases.

The role of cGMP-dependent protein kinase (PKG) in the regulation of rat aortic vascular smooth muscle cells (VSMC) phenotype was examined using a transfected cell culture system. Repetitively passaged VSMC do not express PKG and exist in the synthetic phenotype. Transfection of PKG-l alpha cDNA, or the active catalytic domain of PKG-l alpha, resulted in the appearance of VSMC having a morphology consistent with the contractile phenotype. PKG-expressing cells also contained markers for the contractile phenotype (for example, smooth muscle specific myosin heavy chain, calponin, alpha-actin) and reduced levels of synthetic phenotype markers (osteopontin, thrombospondin). PKG-transfected VSMC have also reduced the levels of fibroblast growth factor receptors 1 and 2, consistent with the establishment of a more contractile phenotype. The regulation of PKG expression in VSMC is largely undefined; however, continuous exposure of cultured bovine aortic smooth muscle cells with nitric oxide (NO)-donor drugs or cyclic nucleotide analogues reduced the expression of PKG. These results suggest that PKG occupies a critical role in VSMC phenotype and that suppression of PKG expression during inflammation or injury promotes a more synthetic state of the VSMC.

Animals↗
PubMed2003

PAI-1 polymorphisms modulate phenotypes associated with the metabolic syndrome in obese and diabetic Caucasian population.

AIM/HYPOTHESIS: Plasminogen activator inhibitor-1 (PAI-1) is a main regulator of the endogenous fibrinolytic system and modulates the thrombosis progression. We analyzed genetic contributions of PAI-1 mutations to the metabolic syndrome and to its complications. METHODS: PAI-1 promoter and coding sequences were screened for mutations. Genotypes were determined for 1067 unrelated individuals of a French Caucasian cohort, selected for diabetes and obesity. Association between PAI-1 polymorphisms and phenotypes related to metabolic syndrome were statistically studied. RESULTS: There were five variants identified: two common polymorphisms, -765 4G/5G and -844 A>G, in the promoter, and three new non-synonymous SNPs, Ala15Thr, Val17Ile and Asn195Ile. In obese non-diabetic subjects, the two promoter polymorphisms were associated with higher fasting glucose concentrations (p=0.006 and p=0.0004, for -765 4G/5G and -844 A>G, respectively) and insulin (p=0.05 and p=0.008, for -765 4G/5G and -844 A>G, respectively). Moreover, the -844 A>G SNP was associated with lower triglyceride (p=0.002) and higher HDL cholesterol concentrations (p=0.02) in lean subjects. In addition, the two promoter and Ala15Thr polymorphisms showed a trend towards association with CHD in diabetic subjects (-765 4G/5G: 0.56/0.51, p=0.05; -844 A>G: 0.63/0.57, p=0.02; Ala15Thr: 0.91/0.88, p=0.04). The SNPs Ala15Thr, located in the PAI-1 signal peptide, and rare the Asn195Ile, located in a beta-sheet structure, could influence conformation of these two structures. CONCLUSIONS/INTERPRETATION: Our results support the hypothesis that PAI-1 polymorphisms probably interact with known environmental risk factors (chronic hyperglycaemia, obesity, etc.) to induce a more severe insulin-resistant metabolic profile in overweight subjects, and to further increase risk for CHD in diabetic subjects.

Body Mass Index↗
PubMed1997

Phenotypic modulation of hamster acinar cells by culture in collagen matrix.

The aim of this study was to assess the effect of different culture conditions on the survival and morphological phenotype of cultured acinar cells. Acinar fragments isolated from hamster pancreas were embedded in rat-tail collagen. Four groups were established: Medium 1-5% NuSerum + basic medium (basic medium = DMEM/F12 supplemented with dexamethasone, 3-isobutyl-2-methylxanthine, and antibiotics); Medium 2-10% NuSerum + basic medium. Medium 3-Medium 2 supplemented with epidermal growth factor and cholera toxin; and Medium 4:-Medium 3 supplemented with soybean trypsin inhibitor. Freshly isolated acinar cells were retrieved morphologically intact. In Medium 1, more than 80% of cells retained a normal histological appearance at 34 days in culture. Immunostaining for amylase was observed at the apical pole of the cells. The remaining cells showed variable degrees of degeneration. In Medium 2, approximately 50% of acinar cells appeared normal at 34 days in culture, while the remainder were severely degenerated. A few cystic structures were also observed. Positive immunostaining for amylase was limited to the cells with a normal histological appearance. The cells grown in Media 3 and 4 had similar courses of morphological changes. After 8 days in culture, most acinar fragments disappeared and were replaced by cystic structures, lined by a single layer of cuboidal cells. Some amylase-positive immunoreactive cells were integral components of the cystic wall. Cellular amylase activity was a function of the different culture media, a more rapid decrease in amylase activity being observed in Media 3 and 4. Uptake of [3H]thymidine did not show any significant differences between the media. It was also found that the ductlike cells cultured in Medium 4 had a limited capacity to redifferentiate into acinar cells. This study shows that the acinar cell phenotype can be maintained in vitro for more than 1 month. This study also suggests that ductal-like epithelial structures arise from transformation of acinar cells.

Amylases↗
PubMed2004

Phenotypic modulation of vascular smooth muscle cells during medial arterial calcification: a role for endothelin?

We have previously shown that an endothelin receptor antagonist can regress medial arterial calcification in a rat model. The aim of this study was to characterize the phenotypic changes of vascular smooth muscle cells during calcification and mineral loss, in order to understand better the underlying mechanisms. Control Wistar rats were compared with rats treated only with warfarin/ vitamin K1 (15 mg/kg per day) for 8 weeks, or in combination with darusentan (30 mg/kg per day) for the final 4 weeks. Vascular smooth muscle cell, bone cell and macrophage phenotypes were evaluated by the local expression of alpha-actin, tartrate-resistant acid phosphatase and ED-1, respectively. Proteins involved in the modulation of bone resorption like osteopontin and osteoprotegerin were also evaluated by immunohistochemistry. The warfarin/vitamin K1 treatment increased medial arterial calcification ninefold (P < 0.05). At sites of calcification, there was a decrease in alpha-actin localization, and an appearance of osteopontin immunostaining. Histochemical and immunostaining for osteoclast and macrophage markers, as well as for osteoprotegerin, were negative. Although the extent of calcification foci was reduced by darusentan, protein localization in the calcified areas was not modified. Thus, the development of medial arterial calcification produces a phenotypic change in vascular smooth muscle cells that does not appear to be normalized in regions remaining calcified during mineral loss.

Animals↗
PubMed1993

Phenotypic modulation and elastin formation of cultured aortic smooth muscle cells grown on and within collagen gels.

Aortic smooth muscle cells (SMC) were grown on and within collagen gels and their phenotype and elastin formation were examined. Cells grown on the gels showed multilayer growth with nodule formation. They contained many ribosomes and microfilament bundles with dense bodies. In contrast, cells grown within collagen gels did not form nodules. When collagen gels containing SMC were manually detached from the culture dish, the cells were found to be of the synthetic phenotype with well-developed rough endoplasmic reticulum (ER) and Golgi complexes, but few microfilament bundles. There were numerous elastin deposits in the intercellular spaces. Our findings suggest that the physical property of the substrate affects the phenotype and function of the SMC.

Animals↗