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Results for “Phenotypic modulation”

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PubMed1997

Novel smooth muscle cell lines from transgenic mice harboring temperature-sensitive SV40 large T-antigen gene. Temperature-dependent expression of smooth muscle myosin heavy chain-1 and calponin genes.

We have established novel vascular smooth muscle cell lines (SVS30 and SVS24 cells) which retain the expression of specific markers for smooth muscle cells, such as alpha-actin, smooth muscle myosin heavy chain-1, and calponin, from transgenic mice harboring the temperature-sensitive SV40 large T-antigen gene. SVS cell lines showed temperature-dependent growth and the expression of SV40 large T-antigen. Interestingly, protein and mRNA levels of smooth muscle myosin heavy chain-1 and calponin seen in culture at the non-permissive temperature (39 degrees C) were higher than those at the permissive temperature (33 degrees C). These results suggest that SV40 large T-antigen affects the expression of smooth muscle-specific markers in SVS cell lines, and that some of the characters in SVS cell lines can be controlled by culture temperature. SVS cell lines should be quite valuable tools with which to study the regulation of phenotypic modulation of smooth muscle cells, and to identify smooth muscle specific transcription factors which involve the expression of smooth muscle myosin heavy chain-1 and calponin genes.

Animals↗

PubMed2000

Mechano-electric feedback in right atrium after left ventricular infarction in rats.

Left ventricular myocardial infarction (MI) can lead to alterations in hemodynamic load conditions, thereby inducing right atrial hypertrophy and dilatation associated with phenotypic modulation of cardiomyocytes, electrical abnormalities, rhythm disturbances, and atrial fibrillation. However, there is limited information on the electrophysiological basis for these events. We investigated whether atrial stretch in the setting of chronic MI modulates the electrophysiological properties of cardiomyocytes via "mechano-electric feedback", providing a mechanism for atrial arrhythmia after ventricular infarction. Five weeks after left ventricular MI (n=37), action potentials (AP) were measured in right atrial tissue preparations using a current clamp scheme, and compared to sham-operated rats (SO, n=10). Contractile activity was recorded at a preload of 1 mN, and sustained stretch was applied via a micrometer. In SO, stretch of 1.75 mN shortened repolarization at 50% and prolonged it at 90%. In MI, mechanically-induced electrical alterations were observed at a significantly lower level of stretch than in SO (0.19 mN). Sustained stretch in MI prolonged AP at 90% repolarization giving rise to stretch-activated depolarizations (SAD) near 90% repolarization (SAD90). When reaching threshold for premature APs, electrical phenomena similar to atrial fibrillations were seen in some preparations. Moreover, we observed APs with prolonged duration at 25%, 50%, and 90% repolarization where stretch induced SAD near 50%. Gadolinium used at a concentration to inhibit stretch-activated channels (40microM) suppressed mechanically-induced electrical events. In conclusion, increased susceptibility after MI to mechanical stretch may predispose atrial cardiomyocytes to arrhythmia. These mechano-electrical alterations are sensitive to gadolinium suggesting involvement of stretch-activated ion channels.

Animals↗

PubMed1997

Regulation of differentiation/maturation in vascular smooth muscle cells by hormones and growth factors.

Smooth muscle cells (SMC) within atherosclerotic lesions show marked alterations in their differentiated properties as compared to normal medial SMC. This process of de-differentiation of SMC has been referred to as "phenotypic modulation", and is characterized by increased growth responsiveness, altered lipid metabolism, increased matrix production, and loss of contractile proteins, all of which can contribute to the development and/or progression of atherosclerotic disease. As such there has been much interest in understanding mechanisms and factors that control the differentiation of the vascular SMC. This paper reviews the effects of growth factors, growth inhibitors, and other extrinsic factors on differentiation/maturation of SMC, with a particular emphasis on consideration of factors that may contribute to abnormal control of SMC differentiation in vascular disease. In addition, we will briefly summarize what is currently known regarding molecular mechanisms that control the coordinate expression of genes encoding for SMC-selective/specific proteins that are required for the differentiated function of the vascular SMC.

Animals↗

PubMed1997

Regulation of angiogenesis by scatter factor.

Scatter factor (SF, hepatocyte growth factor) is a cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. These responses are transduced through a tyrosine kinase receptor that is encoded by a proto-oncogene (c-met). SF is a potent angiogenic molecule, and its angiogenic activity is mediated, in part, through direct actions on endothelial cells. These include stimulation of cell motility, proliferation, protease production, invasion, and organization into capillary-like tubes. SF also stimulates the proliferation of smooth muscle cells and pericytes, cell types that also participate in the formation of capillaries and other microvessels. SF is chronically overexpressed in tumors, and it is postulated SF may function as a tumor angiogenesis factor. SF production in tumors may be due, in part, to an abnormal tumor: stroma interaction in which tumor cells secrete soluble proteins (SF-inducing factors) that stimulate stromal cell SF production and in part to autocrine production by the tumor cells themselves. Recent studies suggest a linkage between tumor suppressors (anti-oncogenes) and inhibition of angiogenesis. We hypothesize that tumor suppressor gene mutations may contribute to activation of an SF-->c-met signalling pathway, leading to an invasive and angiogenic tumor phenotype. Modulation of this pathway may provide clinically useful methods of enhancing or inhibiting angiogenesis.

Adult↗

PubMed2007

Conditional mouse models to study developmental and pathophysiological gene function in muscle.

This chapter will review conditional mouse model systems that have been developed to study gene function in skeletal, cardiac, and vascular smooth muscle cells in vivo with an emphasis on the utility of these models for investigating developmental and pathophysiological gene function in muscle. In general, these systems have utilized muscle-specific/selective promoter-enhancers in conjunction with site-specific DNA recombinases, e.g., Cre-loxP, and fusion proteins with these recombinases that confer temporal control, such as tamoxifen-inducible CreER systems. A major focus of this chapter will be to discuss unique challenges of studying Cre-mediated mutagenesis/gene targeting in these muscle types during development and in the adult animal, some of which are inherent of the muscle cell type being studied. For example, unlike cardiac and skeletal muscle cells, the vascular SMC is extremely plastic and able to undergo rapid phenotypic modulation to various environmental cues in vivo. Thus, employing SMC marker gene promoter enhancers for conditional gene targeting in SMCs must take into account the possibility and/or certainty that the particular SMC promoter enhancers used may or may not be transcriptionally active in SMCs of a vessel wall under normal and some pathophysiological conditions. Moreover, individual floxed loci within the same muscle cell type and tissue have different degrees of sensitivity to Cre, most likely dependent on the chromatin state of that particular gene, i.e., closed/condensed state or open/active state. Thus, Cre recombination may be ineffective for specific floxed gene DNA. Lastly, rigorous efforts must be made to confirm the degree of recombination in a tissue, taking into full account the multicellularity of the tissue, to understand the extent of the physiological effect in that organ.

Animals↗

PubMed1996

Increased tenascin expression is an early feature of the development of transplant renal arteriopathy in humans.

Transplant renal arteriopathy (TRA) is a major obstacle to the long-term survival of human renal allografts. Tenascin (TN) is an extracellular matrix glycoprotein associated with cell growth and differentiation. We investigated TN expression in intrarenal arteries with TRA, in association with cellular components, with phenotypic expression of smooth muscle cells (SMC) and with fibronectin expression. Ten renal allografts that had been removed due to rejection were available. Monoclonal antibodies against SMC, macrophages, T cells, B cells, fibronectin, and TN were used. In the early stages, medial SMC showed a de-differentiated phenotype and the neointima consisted largely of T cells and macrophages. At these stages, increased expression of TN was observed in the media. In later stages, the neointima consisted almost entirely of SMC of a differentiated phenotype and no TN expression was found. Up-regulation of TN may play a role in the migration and phenotypic modulation of SMC at an early stage of TRA in humans.

Actins↗

PubMedDate not supplied

Angiogenic potential of microvessel fragments established in three-dimensional collagen gels.

During angiogenesis, the microvasculature displays both vessel remodeling and expansion under the control of both cellular and extracellular influences. We have evaluated the role of angiogenic and angiostatic molecules on angiogenesis in an in vitro model that more appropriately duplicates the cellular and extracellular components of this process. Freshly isolated microvessel fragments from rat adipose tissue (RFMF) were cultured within three-dimensional collagen I gels. These fragments were characterized at the time of isolation and were composed of vessel segments observed in the microvasculature of fat in situ (i.e., arterioles, venules, and capillaries). Fragments also exhibited characteristic ablumenally associated cells including smooth muscle cells and pericytes. Finally, fragments were encased in an extracellular matrix composed of collagen type IV and collagen type I/III. The elongation of microvascular elements was subsequently evaluated using morphologic and immunocytochemical techniques. The proliferation, migration, and elongation of cellular elements in microvessel fragments from rat adipose tissue was dependent on initial fragment density, matrix density, and required serum. Inclusion of endothelial cell growth factors to microvessel fragments from rat adipose tissue 3-D cultures resulted in the accelerated elongation of tube structures and the expression of von Willebrand factor in cells constituting these tubes. Molecules with reported angiostatic capacity (e.g., transforming growth factor and hydrocortisone) inhibited vessel tube elongation. In vitro methods have been developed to evaluate numerous mechanisms associated with angiogenesis, including endothelial cell proliferation, migration, and phenotypic modulation. Microvascular endothelial cell fragments described in this study represent an in vitro population of cells that accurately duplicate the in vivo microcirculatory elements of fat. The proliferation of cells and elongation of microvascular elements subsequently observed in three-dimensional cultures provides an in vitro model of angiogenesis. Microvascular formation in this system results from pre-existing microvessel fragments unlike tube formation observed when cultured endothelial cells are placed in three-dimensional gels. This form of tube formation from cultured endothelium is more characteristic of vasculogenesis. Thus, the formation of microvascular elements from microvessel fragments provides the opportunity to examine the mechanisms regulating angiogenesis in an in vitro system amenable to precise experimental manipulation.

Actins↗

PubMed2000

Vascular smooth muscle and arterial calcification.

Smooth muscle cultures can calcify under certain circumstances. As a model system these cultures therefore provide information on why calcification occurs in atherosclerotic plaques. Whether all smooth muscle cells (under certain conditions), or only specific populations, can produce this mineralization has not been resolved. Demer's group has cloned calcifying vascular cells from subcultured bovine aorta and studied them in detail. They have speculated on whether the cells are smooth muscle which have altered in phenotype, or whether they are derived from a stem cell population within the artery wall. The article argues that while the normal process of smooth muscle phenotypic modulation seen in arterial repair could account for the observations, this view may be two simplistic considering the complex nature of the artery wall. Certainly there is evidence for heterogeneity of smooth muscle cells in the artery wall and recent evidence suggests that stem cells can circulate in the blood and repopulate tissues. Further studies are required to resolve the important question as to the origin of cells which produce mineralization in atheroma.

Animals↗

PubMed2000

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction.

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity. Expression of myocardial alpha-skeletal actin, beta-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling.

Animals↗

PubMed2002

Identification and genomic organization of gene loci negatively controlled by the virulence regulatory BvgAS two-component system in Bordetella bronchiseptica.

The two-component system BvgAS positively controls transcription of the virulence genes of Bordetella pertussis and B. bronchiseptica, which include several genes for toxins and adhesins. On the other hand, the BvgAS system negatively controls the expression of a poorly characterized set of genes, the so-called virulence repressed ( vrg) genes. To investigate the function of this group of genes and their relationship to virulence, we identified several novel vrg genes of B. bronchiseptica via the generation of transcriptional fusions with gfp (the ORF encoding Green Fluorescent Protein) by transposon mutagenesis. Expression of all of the vrg genes was enhanced under phenotype-modulating growth conditions and in phase variants, demonstrating that their transcription is indeed controlled by the BvgAS system. In addition, transcription of most of these new vrg genes was found to be affected by the growth phase of the bacteria, with maximal expression being observed in the late logarithmic or stationary phase. The majority of these genes encode putative metabolic functions involved in redox reactions and amino acid transport. Interestingly, several vrg genes of B. bronchiseptica are not expressed or have been lost in B. pertussis, indicating that, possibly as a consequence of its adaptation to a single host organism, many vrg genes of B. pertussis are gradually decaying.

Animals↗

PubMed1982

Origin of tubular complexes in human chronic pancreatitis.

Tissue samples from seven patients with chronic pancreatitis were studied by light and electron microscopy, using samples from the pancreas of seven organ donors as a reference group. Tubular complexes were observed in four of the patients with chronic pancreatitis. Tubular complexes, which have been interpreted as resulting from "ductular reduplication" in other studies of chronic pancreatitis, and "ductular proliferation" in studies of pancreatic adenocarcinoma, were studied carefully to determine their origin. Extensive retrogressive changes in acinar cells leading to diminished zymogen granules, decreased cell height, and concomitant increase in luminal diameter were consistent with the interpretation that phenotypic modulation of acinar cells to take on the characteristics of ductular cells produced the tubules. This it is concluded that in chronic pancreatitis, as has been shown for pancreatic adenocarcinoma, the tubular complexes originate from acinar cells rather than from proliferation of preexisting ductules. Fibrosis and thickening of the basal lamina of exocrine pancreatic cells and capillaries were consistent with an altered capability for transmission of material between blood vessels and exocrine cells.

Adult↗

PubMed1991

1,25 (OH)2 vitamin D3 attenuates the loss of resistance artery contractile function associated with incubation in culture media.

Contractile properties of rat mesenteric resistance arteries were studied immediately after isolation or after 48-hr incubation in culture medium [Dulbecco's modified Eagle's/Ham's F-12 (1:1) with insulin, transferrin and antibiotics]. Incubation in culture medium depressed active stress generating capacity, increased sensitivity to norepinephrine and ablated endothelium-dependent relaxation. The decrease in stress generation results from the loss of a releasable pool of intracellular Ca2+; the enhanced sensitivity is associated with decreased neuronal amine pump function. Addition of 300 pg/ml 1,25 (OH)2 vitamin D3 to the culture medium afforded nearly complete protection against the loss of stress generating capacity and partially preserved endothelial function. It is concluded that 1,25 (OH)2 vitamin D3 partially prevents phenotypic modulation of the vascular myocyte induced by culture conditions.

Acetylcholine↗

PubMed1992

Beta-adrenergic responsiveness in cultured aorta smooth muscle cells. Effects of subculture and aging.

beta-Adrenoceptor-mediated vasorelaxation is diminished in vessels from a variety of aged species including humans. This phenomenon was studied for the first time in cultured aorta smooth muscle cells (ASMC) from young (4- to 6-month) and old (24- to 26-month) F-344 rats. Cyclic AMP (cAMP) accumulation was assessed following isoproterenol and forskolin stimulations in primary cultures and after 1-4 passages of aorta smooth muscle cells. Isoproterenol and forskolin increased cAMP accumulation 6- and 10-fold, respectively, in primary cultures from young rats. Isoproterenol stimulation was reduced markedly in passaged cells. Forskolin stimulation was unaffected, indicating passage-related phenotypic changes in receptor-mediated stimulation, but not in post-receptor adenylate cyclase activation. The response to isoproterenol was diminished in old animals, but that to forskolin was unaltered. Thus, cultured ASMC from F-344 rats are highly responsive to beta-adrenoceptor stimulation and demonstrate age-related changes, but undergo phenotypic modulation during passage.

Adenylyl Cyclases↗

PubMed1988

Quantitative ultrastructural analysis of coronary atherosclerotic involvement in two macaque species.

Ultrastructural analyses were employed to observe and to compare in detail lesions of the coronary artery of cynomolgus and rhesus monkeys. Animals were fed individually with the same atherogenic ration under identical conditions for 4, 8, and 12 months, and controls of each species were fed with a low fat, cholesterol-free ration. Transmission electron microscopic studies of coronary arteries from these animals led to the following conclusions: (1) Synthetic smooth muscle cells (SMC) without lipid and macrophages without lipid appeared more frequently in the cynomolgus lesions than in the rhesus lesions. Furthermore, phenotypic expression of synthetic SMCs in the cynomolgus was more active with greater diversity, while the rhesus showed less phenotypic modulation. Macrophages without lipid appeared frequently in the cynomolgus media. (2) Increased percentages of both synthetic SMCs with lipid and macrophages with lipid were demonstrated in the cynomolgus lesions as compared to those in the rhesus. This indicates that foam cells, including SMC- and macrophage-derived foam cells, are more prevalent in cynomolgus than in rhesus. They are considered to play an important role in atherogenesis. (3) Medial disruption, synthetic SMCs, and macrophages containing lipid appeared more often in cynomolgus media than in rhesus media. (4) There were greater percentages of both synthetic SMCs and macrophages in the intima of the myocardial side of coronary arteries in both species. (5) Approximately 42% of all foam cells in the cynomolgus lesions were derived from SMCs. There were fewer macrophages in rhesus lesions. (6) The difference in expression between the two macaque species reflects different responses of macrophages to medial smooth muscle cell (SMC) components. The configuration of the artery wall could be one of the important indicators of these different expressions.

Animals↗

PubMed1988

Inhibitory effect of dimethyl sulfoxide on the proliferation of cultured arterial smooth muscle cells: relationship to the cytoplasmic microtubules.

Our preliminary study has shown that dimethyl sulfoxide (DMSO) has an inhibitory effect on the proliferation of cultured arterial smooth muscle cells and promotes phenotypic modulation from the synthetic state to the contractile state. In the present study we have examined the effect of DMSO with special attention to relationship between cell growth and cytoplasmic microtubules. DMSO inhibited DNA synthesis and cell division, and concomitantly promoted microtubule assembly. Initiation of DNA synthesis and cell division of nonproliferating cells by platelet-derived growth factor (PDGF) was also inhibited in the presence of 1% DMSO. A 12-hr incubation with 10(-6) M colchicine caused disruption of microtubules; however, pretreatment with 1% DMSO for 24 hr prevented the disruption, indicating that DMSO has a stabilizing action on microtubules. A 24-hr exposure to PDGF resulted in microtubule depolymerization, while the addition of 1% DMSO prevented the depolymerization. These results suggest that DMSO inhibits DNA synthesis of cultured smooth muscle cells by stabilizing cytoplasmic microtubules.

Animals↗

PubMed1991

Type I collagen fibrils promote rapid vascular tube formation upon contact with the apical side of cultured endothelium.

Extracellular matrix (ECM) components phenotypically modulate cultured endothelium. This paper examined the ability of ECM components to promote tube formation in vitro. When collagen type I was added to the culture medium of confluent neonatal foreskin or human umbilical vein endothelium at 10-100 micrograms/ml tube-like structures formed rapidly. Tube formation did not occur with the addition of other ECM components at similar concentrations. Electron microscopy revealed that the lumen of the tubes consisted of collagen fibrils, with the surrounding cells having typical endothelial junctional complexes. These findings demonstrate that when collagen fibrils make contact with the apical side of endothelium they act as a stimulus and provide a template for vascular tube formation.

Collagen↗

PubMed1987

Smooth muscle cell proliferation in the rat coronary artery induced by vitamin D.

Ultrastructural changes induced in rat coronary arteries by oral administration of a large dose of vitamin D2 were examined by transmission and scanning electron microscopy. Our observations were that smooth muscle cell proliferation occurred without endothelial denudation and without exposure of the subendothelium. While the endothelial cells did show evidence of degeneration, the adjoining endothelial cells migrated beneath so that these degenerated cells could become detached without exposing the subendothelium. Therefore, factors other than platelets seem to participate in the phenotypic modulation and proliferation of the smooth muscle cell. Medial degeneration may be a prerequisite for formation of the lesion.

Administration, Oral↗

PubMed1993

Monocyte/macrophage accumulation and smooth muscle cell phenotypes in early atherosclerotic lesions of human aorta.

In a search for early atherosclerotic lesions, we have investigated grossly normal areas of human thoracic aortas taken at autopsy from 40 trauma victims aged from 3 to 40 years. Two areas of aorta were compared: lesion predisposed to atherosclerosis (LP) area localized on the dorsal aspect of the vessel along the row of intercostal branching sites, and lesion resistant (LR) area located on the ventral aspect of the vessel. Accumulation of apolipoprotein B (apo B) was found in LP aortic area of each child older than 6 years. Similar retention of apo B in LR area appeared only in aortas of teenagers. The apo B staining increased with age in both areas tested but was usually of a greater extent in LP area than in LR area. Typical smooth muscle cells (SMCs) and a few monocytes/macrophages (Mn/Mph) were revealed in the intimal layer of all aortas examined. The number of Mn/Mph dramatically increased in LP areas of individuals over 17 years. Quantitative study of double stained sections has shown a 2- to 6-fold enhanced number of Mn/Mph in LP area compared with LR aortic area of 10 men over 21 years. Focal infiltration of Mn/Mph in aortas of young adults occurred without endothelial denudation. In addition, some intimal SMCs in LP area of 12 aortas out of 29 expressed desmin and contained well-developed endoplasmic reticulum, while such cells were seldom detected in LP area of the vessels. Thus, focal accumulation of apo B with subsequent Mn/Mph infiltration and SMC phenotypic modulation in LP aortic area of young adults may be causally involved in fatty streak and atherosclerotic plaque formation.

Adolescent↗