Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Becaplermin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 883 records · Page 49Linked to original sources
PubMed2000

PDGF-beta receptor expression and ventilatory acclimatization to hypoxia in the rat.

Activation of platelet-derived growth factor-beta (PDGF-beta) receptors in the nucleus of the solitary tract (nTS) modulates the late phase of the acute hypoxic ventilatory response (HVR) in the rat. We hypothesized that temporal changes in PDGF-beta receptor expression could underlie the ventilatory acclimatization to hypoxia (VAH). Normoxic ventilation was examined in adult Sprague-Dawley rats chronically exposed to 10% O(2), and at 0, 1, 2, 7, and 14 days, Northern and Western blots of the dorsocaudal brain stem were performed for assessment of PDGF-beta receptor expression. Although no significant changes in PDGF-beta receptor mRNA occurred over time, marked attenuation of PDGF-beta receptor protein became apparent after day 7 of hypoxic exposure. Such changes were significantly correlated with concomitant increases in normoxic ventilation, i.e., with VAH (r: -0.56, P < 0.005). In addition, long-term administration of PDGF-BB in the nTS via osmotic pumps loaded with either PDGF-BB (n = 8) or vehicle (Veh; n = 8) showed that although no significant changes in the magnitude of acute HVR occurred in Veh over time, the typical attenuation of HVR by PDGF-BB decreased over time. Furthermore, PDGF-BB microinjections did not attenuate HVR in acclimatized rats at 7 and 14 days of hypoxia (n = 10). We conclude that decreased expression of PDGF-beta receptors in the dorsocaudal brain stem correlates with the magnitude of VAH. We speculate that the decreased expression of PDGF-beta receptors is mediated via internalization and degradation of the receptor rather than by transcriptional regulation.

Adaptation, Physiological↗
PubMed2005

Synergistic effects of PDGF-BB and cAMP-elevating agents on expression of connexin43 in mesangial cells.

The gap junction plays an important role in the regulation of cell growth, migration, and differentiation. Platelet-derived growth factor (PDGF) is reported to be a potent inhibitor of gap junctional intercellular communication (GJIC). Short-term exposure of cells to PDGF causes rapid and transient disruption of GJIC without altering connexin43 (Cx43) protein level. In this study, we investigated long-term effects of PDGF-BB on Cx43 expression in mesangial cells (MCs). Exposure of MCs to PDGF-BB affected neither the Cx43 protein level nor GJIC. However, in the presence of cAMP-elevating agents, PDGF-BB dramatically increased the expression of Cx43, which was accompanied by obviously augmented membrane distribution of Cx43 and functional GJIC. The increased expression of Cx43 was closely correlated with reduction in alpha-actin, a dedifferentiation marker of MCs. The effect of PDGF on Cx43 was largely prevented by inhibitors of phosphatidylinositol 3'-kinase or mitogen-activated protein kinase, but not by inhibition of protein kinase C. Exposure of MCs to PDGF-BB caused elevation in intracellular cAMP, and it was abolished by indomethacin, a cyclooxygenase inhibitor. However, indomethacin did not affect the synergistic effect. In addition, PDGF-BB also did not affect the degradation of Cx43. With the use of MCs transfected with a Cx43 promoter-luciferase vector, cooperative activation of Cx43 promoter by PDGF and cAMP was found. Together, our data reveal, for the first time, unexpected synergy between PDGF-BB and cAMP-elevating agents in the induction of Cx43 and MC differentiation. Regulation of GJIC could be an important mechanism via which PDGF modulates MC phenotypes.

Animals↗
PubMed2002

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H(2)O(2) and PDGF in mesangial cells.

Increased prostaglandin production is implicated in the pathogenesis of glomerular disease. With this consideration, we examined the combined effects of reactive oxygen species and platelet-derived growth factor (PDGF), which might initiate glomerular dysfunction, on arachidonic acid release and cytosolic phospholipase A(2) (cPLA(2)) activation in rat mesangial cells. H(2)O(2)-induced release of arachidonic acid was enhanced by PDGF, which by itself had little effect on the release, and the enhancement was completely inhibited by a cPLA(2) inhibitor. The phosphorylation of cPLA(2), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein (MAP) kinase was upregulated by H(2)O(2) or PDGF alone and except for ERK was enhanced further by the two in combination. The release of arachidonic acid induced by PDGF together with H(2)O(2) was inhibited partially by an inhibitor of ERK or p38 MAP kinase and completely when the two inhibitors were combined; the inhibitory pattern was similar to that for the phosphorylation of cPLA(2). These results suggest that the ERK and p38 MAP kinase pathways are involved in the increase in cPLA(2) activation and arachidonic acid release induced by PDGF together with H(2)O(2).

Animals↗
PubMed2003

Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model.

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT(1)R). Recent studies have suggested that type 2 receptor (AT(2)R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT(1)R. The aim of the present study was to determine the effect of AT(2)R overexpression on glomerular injury induced by (5/6) nephrectomy ((5/6)Nx). AT(2)R transgenic mice (AT(2)-Tg), overexpressing AT(2)R under the control of alpha-smooth muscle actin (alpha-SMA) promoter, and control wild-type mice (Wild) were subjected to (5/6)Nx. In AT(2)-Tg mice, the glomerular expression of AT(2)R was upregulated after (5/6)Nx. Urinary albumin excretion at 12 wk after (5/6)Nx was decreased by 33.7% in AT(2)-Tg compared with Wild mice. Glomerular size in AT(2)-Tg mice was significantly smaller than in Wild mice after (5/6)Nx (93.1 +/- 3.0 vs. 103.3 +/- 1.8 microm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-beta(1) (TGF-beta(1)) in AT(2)-Tg with (5/6)Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT(2)-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-beta(1), was decreased in AT(2)-Tg mice. These changes in AT(2)-Tg mice at 12 wk after (5/6)Nx were blocked by the AT(2)R antagonist PD-123319. Taken together, our findings suggest that AT(2)R-mediated signaling may protect from glomerular injuries induced by (5/6)Nx and that overexpression of AT(2)R may serve as a potential therapeutic strategy for glomerular disorders.

Actins↗
PubMed2002

Effect of platelet-derived growth factor isoforms in rat metanephric mesenchymal cells.

Platelet-derived growth factor (PDGF) B-chain or PDGF beta-receptor-deficient mice lack mesangial cells. To explore potential mechanisms for failure of PDGF A-chain to rescue mesangial cell phenotype, we investigated the biological effects and signaling pathways of PDGF AA and PDGF BB in metanephric mesenchymal (MM) cells isolated from rat kidney. PDGF AA caused modest cell migration but had no effect on DNA synthesis, unlike PDGF BB, which potently stimulated migration and DNA synthesis. PDGF AA and PDGF BB significantly increased the activities of phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK). PDGF BB was more potent than PDGF AA in activating PI 3-K or MAPK in these cells. Pretreatment of MM cells with the MAPK kinase (MEK) inhibitor PD-098059 abrogated PDGF BB-induced DNA synthesis, whereas the PI 3-K inhibitor wortmannin had a very modest inhibitory effect on DNA synthesis (approximately Delta20%). On the other hand, wortmannin completely blocked PDGF AA- and PDGF BB-induced migration, whereas PD-098059 had a modest inhibitory effect on cell migration. These data demonstrate that activation of MAPK is necessary for the mitogenic effect of PDGF BB, whereas PI 3-K is required for the chemotactic effect of PDGF AA and PDGF BB. Although PDGF AA stimulates PI 3-K and MAPK activity, it is not mitogenic and only modestly chemotactic. Collectively, the data may have implications related to the failure of PDGF AA to rescue mesangial cell phenotype in PDGF B-chain or PDGF-beta-receptor deficiency.

Animals↗
PubMed1994

Endothelin modulates the mitogenic effect of PDGF on glomerular mesangial cells.

We showed that two isoforms of platelet-derived growth factor (PDGF), AB and BB, stimulate the secretion of endothelin (ET)-1 from cultured rat mesangial cells. Then, we examined whether PDGF AB and BB stimulate mesangial cell proliferation through the modulation of the endogenous production of ET-1 in these cells. Mitogenesis experiments were assessed by tritiated thymidine incorporation into DNA under highest concentrations (10 ng/ml) of PDGF AB and BB in the presence and absence of anti-ET-1 antiserum or a selective A-type endothelin receptor (ETA receptor) antagonist, BQ-123. PDGF AB and BB potently stimulate thymidine incorporation. This stimulation was significantly attenuated in the presence of either anti-ET-1 antiserum or BQ-123 (10(-7)-10(-5)M). Results suggest that PDGF AB and BB stimulate ET-1 secretion in rat mesangial cells through PDGF beta-receptors, and endogenously produced ET-1 serves to modulate the mitogenic effect of PDGF AB and BB, probably via ETA receptors in these cells.

Animals↗
PubMed1996

Sustained ERK-2 activation in rat glomerular mesangial cells: differential regulation by protein phosphatases.

The duration of extracellular signal-regulated protein kinase (ERK) activation is critical for cell signaling decisions and probably determines whether a stimulus elicits proliferation or differentiation. We studied the intracellular signals regulating sustained ERK-2 activity in glomerular mesangial cells (GMC), utilizing combination of GMC mitogens of different potency. Incubation of GMC with both endothelin-1 (ET-1) and platelet-derived growth factor BB (PDGF-BB) led to a long-lasting, monophasic increase in ERK-2 activity. In contrast, when ET-1 was administered together with epidermal growth factor (EGF), a less pronounced and shorter activation occurred. Long-term stimulation of ERK-2 was accompanied by an increase in p45 MEK activity, which again was more pronounced when ET-1 was administered together with PDGF-BB compared with EGF. In the presence of actinomycin D (Act D), an inhibitor of RNA synthesis, ERK-2 activity induced by ET-1 and PDGF-BB but not by ET-1 and EGF remained elevated more than sixfold throughout the whole incubation period of 6 h. The effect of Act D on ET-1- and PDGF-BB-induced ERK-2 activation was mimicked by the protein phosphatase inhibitor sodium orthovanadate. In addition, vanadate also unmarked an ET-1- and EGF-induced ERK-2 activity after 6 h. The serine/threonine phosphatase inhibitor okadaic acid (OA) did neither alter agonist-induced ERK-2 activity after 6 h (0.5 nM OA) nor after 10 min or 1 h (250 nM). Together these results suggest that, in GMC, long-term activation of the mitogen-activated protein kinase ERK-2 is differentially regulated, depending on the combination of agonists administered. ET-1- and PDGF-BB-induced long-term activation of ERK-2 is regulated by a vanadate-sensitive protein phosphatase(s) and by a transcriptionally regulated protein(s). In contrast, ET-1- and EGF-induced sustained ERK-2 stimulation is regulated by a vanadate-sensitive protein phosphatase(s) but not by a transcriptionally regulated protein. Agonist-specific and time-dependent stimulation of ERK-2-regulating protein phosphatases may be critical for the length of ERK-2 activation in GMC and could thus be of pathophysiological significance in glomerular diseases associated with alterations in cell proliferation or cell differentiation.

Animals↗
PubMed1996

Regulation of PDGF-beta receptor-operated Ca2+ channels by phospholipase C-gamma 1 in glomerular mesangial cells.

Platelet-derived growth factor (PDGF)-induced Ca2+ signaling mechanisms were examined in cultured rat glomerular mesangial cells. PDGF-BB stimulated the tyrosine phosphorylation of phospholipase C (PLC)-gamma 1, the formation of a PLC-gamma 1/PDGF-beta receptor membrane complex, and the generation of intracellular inositol 1,4,5-trisphosphate (IP3). Preincubation with a tyrosine kinase inhibitor (genistein) abolished these PDGF-induced responses. Activation of 1-pS Ca2+ channels in cell-attached patches by intrapipette PDGF-BB was also abolished by tyrosine kinase inhibition. In the absence of PDGF-BB, channels were activated in cell-attached patches exposed to intrapipette thapsigargin (IP3-independent releaser of intracellular Ca2+ stores) and in excised inside-out patches exposed to increasing "cytoplasmic" Ca2+ (10(-8) to 10(-6) M). In cell-attached patches, channel activation by PDGF-BB was abolished when extracellular Ca2+ was < 1 mM. In glomerular mesangial cells 1) PDGF-BB stimulates tyrosine phosphorylation of PLC-gamma 1, PDGF-beta receptor/PLC-gamma 1 membrane complex formation, IP3 production, and 1-pS Ca2+ channel activity; 2) all four PDGF-induced responses are abolished by tyrosine kinase inhibition; 3) PDGF receptor-operated Ca2+ channels are sensitive to both intra- and extracellular Ca2+.

Animals↗
PubMed1998

Potential autocrine and paracrine mechanisms of recovery from mechanical injury of renal tubular epithelial cells.

The present studies were done to clarify potential pathways of the nephrogenic repair process. Media removed from mechanically injured vascular smooth muscle cells and LLC-PK1 renal tubular epithelial cells significantly stimulated [3H]thymidine uptake and cell number in quiescent LLC-PK1 cells, demonstrating the existence of potential autocrine and paracrine pathways of nephrogenic repair. The effect of mechanical injury resulting in release of one or more growth factors into culture media was also found in the opossum kidney OK renal tubular cell line. The nonspecific peptide growth factor antagonist suramin inhibited the effect of media from injured LLC-PK1 cells to stimulate [3H]thymidine uptake in quiescent LLC-PK1 cells. Exposure of quiescent LLC-PK1 cells to six growth factors, including acidic and basic fibroblastic growth factors (aFGF and bFGF), platelet-derived growth factors AA and BB (PDGF-AA and PDGF-BB), endothelin-2, and hepatocyte growth factor, reproduced the biological responses seen when quiescent LLC-PK1 cells were exposed to media from injured cells. Immunoblotting and enzyme-linked immunosorbent assay experiments demonstrated the presence of aFGF, bFGF, and PDGF-BB but not other candidate growth factors in the media from injured LLC-PK1 cells. A neutralizing antibody directed against bFGF attenuated the effect of media from injured cells to stimulate [3H]thymidine uptake in serum-starved LLC-PK1 cells. These results demonstrate that mechanical injury to renal tubular epithelial cells results in release of aFGF, bFGF, and PDGF-BB into the media and suggests that bFGF may be involved in an autocrine fashion to promote recovery from injury.

Animals↗
PubMed2003

Effects of hypoxia on rat airway smooth muscle cell proliferation.

Although it is well known that hypoxemia induces pulmonary vasoconstriction and vascular remodeling, due to the proliferation of both vascular smooth muscle cells and fibroblasts, the effects of hypoxemia on airway smooth muscle cells are not well characterized. The present study was designed to assess the in vitro effects of hypoxia (1 or 3% O(2)) on rat airway smooth muscle cell growth and response to mitogens (PDGF and 5-HT). Cell growth was assessed by cell counting and cell cycle analysis. Compared with normoxia (21% O(2)), there was a 42.2% increase in the rate of proliferation of cells exposed to 3% O(2) (72 h, P = 0.006), as well as an enhanced response to PDGF (13.9% increase; P = 0.023) and to 5-HT (17.2% increase; P = 0.039). Exposure to 1% O(2) (72 h) decreased cell proliferation by 21.0% (P = 0.017) and reduced the increase in cell proliferation induced by PGDF and 5-HT by 16.2 and 15.7%, respectively (P = 0.019 and P = 0.011). A significant inhibition in hypoxia-induced cell proliferation was observed after the administration of bisindolylmaleimide GF-109203X (a specific PKC inhibitor) or downregulation of PKC with PMA. Pretreatment with GF-109203X decreased proliferation by 21.5% (P = 0.004) and PMA by 31.5% (P = 0.005). These results show that hypoxia induces airway smooth muscle cell proliferation, which is at least partially dependent on PKC activation. They suggest that hypoxia could contribute to airway remodeling in patients suffering from chronic, severe respiratory diseases.

Animals↗
PubMed2004

Mechanical stretch is a highly selective regulator of gene expression in human bladder smooth muscle cells.

Application of mechanical stimuli has been shown to alter gene expression in bladder smooth muscle cells (SMC). To date, only a limited number of "stretch-responsive" genes in this cell type have been reported. We employed oligonucleotide arrays to identify stretch-sensitive genes in primary culture human bladder SMC subjected to repetitive mechanical stimulation for 4 h. Differential gene expression between stretched and nonstretched cells was assessed using Significance Analysis of Microarrays (SAM). Expression of 20 out of 11,731 expressed genes ( approximately 0.17%) was altered >2-fold following stretch, with 19 genes induced and one gene (FGF-9) repressed. Using real-time RT-PCR, we tested independently the responsiveness of 15 genes to stretch and to platelet-derived growth factor-BB (PDGF-BB), another hypertrophic stimulus for bladder SMC. In response to both stimuli, expression of 13 genes increased, 1 gene (FGF-9) decreased, and 1 gene was unchanged. Six transcripts (HB-EGF, BMP-2, COX-2, LIF, PAR-2, and FGF-9) were evaluated using an ex vivo rat model of bladder distension. HB-EGF, BMP-2, COX-2, LIF, and PAR-2 increased with bladder stretch ex vivo, whereas FGF-9 decreased, consistent with expression changes observed in vitro. In silico analysis of microarray data using the FIRED algorithm identified c-jun, AP-1, ATF-2, and neurofibromin-1 (NF-1) as potential transcriptional mediators of stretch signals. Furthermore, the promoters of 9 of 13 stretch-responsive genes contained AP-1 binding sites. These observations identify stretch as a highly selective regulator of gene expression in bladder SMC. Moreover, they suggest that mechanical and growth factor signals converge on common transcriptional regulators that include members of the AP-1 family.

Algorithms↗
PubMed2004

Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate.

Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF beta-receptor and was thus dependent on host PDGF beta-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.

Animals↗
PubMed2004

Activation of the platelet-derived growth factor-receptor enhances survival of murine bone endothelial cells.

The activation of the microvascular endothelial cell platelet-derived growth factor (PDGF) receptor (PDGF-R) by PDGF has been implicated in neoplastic angiogenesis. Here, we established cultures of murine bone microvascular endothelial cells and examined their response to stimulation with PDGF BB ligand and to blockade of PDGF-R signaling with the tyrosine kinase inhibitor STI571 (Gleevec). The addition of STI571 to cultures of bone endothelial cells blocked PDGF BB-induced phosphorylation in a dose-dependent manner and completely abrogated the activation of downstream targets Akt and ERK1/2. Coadministration of STI571 and Taxol also induced the activation of procaspase-3 and significant apoptosis. These data suggest that phosphorylation of PDGF-R stimulates survival pathways in bone endothelial cells and that by selectively inhibiting PDGF-R signaling with STI571, the cells are rendered sensitive to Taxol treatment. The therapeutic combination of STI571 and Taxol may be a powerful tool for targeting tumor-associated endothelial cells in the skeletal compartment.

Animals↗
PubMed2005

Targeting the platelet-derived growth factor receptor alpha with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: implications as a potential therapeutic target.

Platelet-derived growth factor receptor alpha (PDGFRalpha) is a type III receptor tyrosine kinase that is expressed on a variety of tumor types. A neutralizing monoclonal antibody to human PDGFRalpha, which did not cross-react with the beta form of the receptor, was generated. The fully human antibody, termed 3G3, has a Kd of 40 pmol/L and blocks both PDGF-AA and PDGF-BB ligands from binding to PDGFRalpha. In addition to blocking ligand-induced cell mitogenesis and receptor autophosphorylation, 3G3 inhibited phosphorylation of the downstream signaling molecules Akt and mitogen-activated protein kinase. This inhibition was seen in both transfected and tumor cell lines expressing PDGFRalpha. The in vivo antitumor activity of 3G3 was tested in human glioblastoma (U118) and leiomyosarcoma (SKLMS-1) xenograft tumor models in athymic nude mice. Antibody 3G3 significantly inhibited the growth of U118 (P=0.0004) and SKLMS-1 (P <0.0001) tumors relative to control. These data suggest that 3G3 may be useful for the treatment of tumors that express PDGFRalpha.

Animals↗
PubMed1998

Eicosapentaenoic acid inhibits mitogen-induced endothelin-1 production and DNA synthesis in cultured bovine mesangial cells.

The present study was designed to examine whether eicosapentaenoic acid (EPA) inhibits the production of basal or stimulated endothelin (ET)-1 by platelet-derived growth factor (PDGF)-BB or epidermal growth factor (EGF), and DNA synthesis in cultured bovine mesangial cells. PDGF-BB and EGF stimulated ET-1 secretion in a dose-dependent fashion in these cells. EPA (10-100 microM) exhibited dose-related inhibition of PDGF-BB- and EGF-stimulated ET-1 secretion. EPA had no inhibitory effects on basal ET-1 secretion in these cells. Moreover, 50 microM EPA significantly attenuated PDGF-BB- and EGF-stimulated [3H]thymidine incorporation into mesangial cells. Receptor-binding experiments showed that EPA competitively inhibited 125I-PDGF-BB or 125I-EGF binding to mesangial cell surface receptors. Scatchard analysis for PDGF-BB receptor or EGF receptor revealed a linear regression fit and one binding site. Pretreatment with 50 microM EPA suppressed the number of maximum binding sites, but did not affect the Kd values. These results indicate that EPA potentially inhibits mesangial cell ET-1 production, when stimulated by PDGF-BB or EGF. This inhibitory effect of EPA could be related to the attenuation of mesangial cell proliferation via inhibition of the binding of PDGF-BB or EGF to their receptors due to alteration of the physicochemical characteristics of the cell membrane.

Animals↗
PubMed2000

Regulation of neuronal differentiation in human CNS stem cell progeny by leukemia inhibitory factor.

The generation of diverse types of neural cells during development occurs through the progressive restriction of the fate potential of neuroepithelial progenitor cells. This process is controlled by factors intrinsic and extrinsic to the cell. While the effect of extrinsic cues on multipotent stem cells of the murine central nervous system (CNS) is becoming clearer, little is known of neural stem cells of human origin. We sought to establish the roles played by two cytokines, leukemia inhibitory (LIF) and ciliary neurotrophic factor (CNTF), and by nerve growth factor (NGF) and platelet-derived growth factor (PDGF) in regulating neuronal and astroglial differentiation in cultured embryonic diencephalic human stem cells. While NGF did not influence either neuronal or glial formation, PDGF surprisingly decreased the percentage of stem cell-generated neurons, an effect opposite to that observed in murine progenitors. Furthermore, while we confirmed the known ability of LIF and CNTF to support astroglial differentiation, we also observed that, in contrast with their murine counterparts, the fraction of CNS stem cell-generated neurons in human cultures was enhanced twofold in the presence of both cytokines. These findings highlight important differences between humans and rodents in regard to the way epigenetic cues regulate the function of neural stem cells.

Astrocytes↗
PubMed2000

Expressions of various growth factors and their receptors in tissues from neurofibroma.

BACKGROUND: Platelet-derived growth factor BB (PDGF-BB) and transforming growth factor beta are known to enhance the growth of neurofibroma-derived cells from neurofibromatosis type 1 (NF-1) patients. OBJECTIVE: This study aims to elucidate whether these growth factors and their receptors are up-regulated in NF-1 patients. METHODS: Tissues and culture cells from neurofibroma in NF-1 patients, nontumor lesions in NF-1 patients, and the skin of normal controls were collected. To evaluate the expressions of growth factors and their receptors, reverse-transcriptase polymerase chain reaction and immunohistochemistry were performed. RESULTS: PDGF-beta receptor subunit was expressed in the neurofibroma tissues from NF-1 patients, but not in the nontumorous tissues from NF-1 patients or skin from normal controls. As for the other factors, there were no significant differences among these tissues. Neurofibroma sections also stained positive for the PDGF-beta receptor subunit. CONCLUSIONS: The interaction of PDGF and PDGF-beta receptor subunit may be important in the tumorigenesis of NF-1.

Becaplermin↗
PubMedDate not supplied

Heparin fails to inhibit the proliferation of human vascular smooth muscle cells in the presence of human serum.

The proliferation of vascular smooth muscle cells (VSMC) plays a significant part in both the developing atherosclerotic lesion and in restenosis. Heparin has been widely reported to inhibit the growth of VSMC in culture and intimal VSMC in some animal models of vascular hyperplasia. Clinical trials with heparin, however, have failed to inhibit restenosis following angioplasty. Bovine serum is normally used as a growth supplement in in vitro VSMC growth assays. We have compared the effects of human serum with those of bovine serum on the cellular response to heparin in human VSMC culture. While heparin inhibited the proliferation of human VSMC in the presence of bovine serum, it was totally ineffective in the presence of human serum. These observations were consistent over a wide range of serum and VSMC samples. Experiments utilizing neutralizing antibodies to a number of growth factors showed that cells in either serum were similarly dependent on platelet-derived growth factor for proliferation. In contrast, proliferation in the presence of bovine serum was shown to be dependent on extracellular basic fibroblast growth factor, whereas that in human serum was not. Direct binding of [3H]-heparin to VSMC was significantly reduced in the presence of human serum compared with bovine serum, and the former contained twice the concentration of heparin-binding factors of the latter. Removal of heparin-binding factors from either serum type significantly reduced the proliferation potential. Fractionation of heparin-binding factors from human serum showed that the major growth-promoting activity, together with heparin resistance, was contained within a fraction excluded by a 100,000 molecular weight membrane. We conclude that the mechanism of resistance to heparin in human serum is likely to be due to a combination of differential growth factor binding and interference with heparin interaction with cellular receptors by a high molecular weight heparin-binding factor. This phenomenon may significantly contribute to the lack of success of heparin as an antirestenotic agent in clinical trials.

Animals↗