A plasticity for blood vessel remodeling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF.
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Becaplermin↗
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Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action.
Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation. Because ethanol inhibits cell proliferation in vivo and in vitro, we hypothesize that ethanol-induced inhibition results from differential interference with signal transduction pathways activated by PDGF. Cultured cortical astrocytes were used to examine the effects of ethanol on PDGF-mediated signal transduction, on the expression of two PDGF monomers (A- and B-chains), and on the expression of two PDGF receptor subunits (PDGFalphar and PDGFbetar). PDGF-B chain homodimer (PDGF-BB), and to a lesser extent PDGF-A chain homodimer (PDGF-AA), stimulated the proliferation of astrocytes raised in a serum-free medium. Ethanol attenuated these actions in a concentration-dependent manner. Ethanol inhibited both PDGF-AA- and PDGF-BB-mediated phosphorylation of PDGFalphar, but it had little effect on PDGFbetar autophosphorylation. Likewise, ethanol abolished the association of PDGFalphar to Ras GTPase-activating protein (Ras-GAP), but it did not affect the binding of Ras-GAP to PDGFbetar. PDGF stimulated the activities of mitogen-activated protein kinase (MAPK) in protein kinase C (PKC) independent and dependent manners. Ethanol inhibited the PKC-independent, acute activation of MAPK; however, it stimulated the PKC-dependent, sustained activation of MAPK. The expression of neither ligand was altered by exposure to ethanol for 3 d. Moreover, such treatment specifically upregulated PDGFalphar expression in a concentration-dependent manner. It did not, however, affect the binding affinity of either receptor. Thus, the signal transduction pathways initiated by PDGF-AA and PDGF-BB were differentially affected by ethanol. This differential vulnerability resulted from the preferential effects of ethanol on PDGFalphar autophosphorylation. Hence, ethanol-induced alterations are transduced through specific receptors of mitogenic growth factors.
Animals↗
Cytokine regulation of hyaluronate production by human Tenon's capsule fibroblasts.
PURPOSE: The high-molecular weight glycosaminoglycan hyaluronate (HA), a component of the extracellular matrix, has been shown to play important roles in many biological processes including cell proliferation, migration and differentiation. In the present study, the effect of cytokines on production of hyaluronate (HA) by human tenon's capsule fibroblasts (HTF) was determined. METHODS: HTF (2(nd) passage) were seeded at a cell density of 30 cells/mm(2) and stimulated by six different cytokines (platelet-derived growth factor (PDGF)-AA, PDGF-BB, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), interleukin (IL)-1beta and transforming growth factor (TGF)-beta1). Controls were treated with aliquots of serum-free medium only. Concentrations of HA were determined using a radiometric assay based on the specific binding of HA to HA binding proteins. RESULTS: The concentration of HA in conditioned medium of HTF was significantly increased only after stimulation with PDGF-AA [10 and 100ng/ml], IL-1beta [1 and 10ng/ml] and TGF-beta1 [5ng/ml]. CONCLUSIONS: Production of HA by HTF is regulated by PDGF-AA, IL-1beta and TGF-beta1 and is speculated to be involved in the wound healing reaction after glaucoma filtration surgery.
Becaplermin↗
Platelet-derived growth factor is a principal inductive factormodulating mannose 6-phosphate/insulin-like growth factor-II receptorgene expression via a distal E-box in activated hepatic stellate cells.
Hepatic stellate cells (HSCs) become activated during the earlystages of hepatic injury associated with fibrogenesis. The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGFIIR) plays animportant role in early fibrogenesis by participating in the activationof latent transforming growth factor-beta, a potent inducer of thematrix proteins in activated stellate cells that produce the hepaticnodule. Platelet-derived growth factor (PDGF), a potent HSC mitogen, isreleased early in hepatic injury and activates several signallingpathways in HSCs. In this study we examined the role of PDGF-BB in HSCregulation of M6P/IGFIIR gene expression. Several promoter elementswere found and characterized that modulate M6P/IGFIIR expression inactivated stellate cells. The presence of a distal CACGTG E-box at-2695 was required for M6P/IGFIIR expression in transfectedstellate cells. When the distal E-box was removed there was no significant M6P/IGFIIR promoter activity. The distal E-box-binding protein responded specifically to PDGF-BB with increased binding. This coincided with PDGF-BB up-regulation of M6P/IGFIIR mRNA transcript levels. Downstream elements include two proximal (-2 to-48) CACGTG E-boxes that bind a different protein to the distal(-2695) E-box. The proximal E-boxes respond moderately to PDGF-BB. The promoter segment encompassing -144 to +109 is able to respond dramatically to serum but is refractory to PDGF-BB. However, a constitutively bound protein binding to the -611/-716 fragment appears to be a repressor that suppresses inductive changes in protein binding occurring downstream of -611. These results indicate that the M6P/IGFIIR promoter responds primarily and specifically to PDGF-BB through a distal E-box element and possibly through two proximal E-box elements.
Animals↗
Extracellular-signal regulated kinase signaling pathway mediates downregulation of type I procollagen gene expression by FGF-2, PDGF-BB, and okadaic acid in osteoblastic cells.
Although basic fibroblast growth factor (FGF-2) had been shown to inhibit type I collagen gene expression in osteoblast, its inhibitory mechanism is unknown. In the present study, we investigated the underlying mechanisms by which growth factors downregulate type I collagen gene expression. Treatment of mouse osteoblastic MC3T3-E1 cells with okadaic acid (40 ng/ml), an inhibitor of phosphoserine/threonine-specific protein phosphatase and activator of ERK1/2, for 24 h and 48 h completely inhibited steady-state mRNA levels of type I collagen. FGF-2 (30 ng/ml), platelet-derived growth factor-BB (PDGF-BB), 30 ng/ml, and serum, which activate ERK mitogen-activated protein kinase (MAPK) pathway also inhibited collagen type I gene expression, suggesting that the activation of ERK pathway mediates inhibition of type I collagen mRNA. This observation was further confirmed by experiments using inhibitors of the ERK pathway (i.e., PD and U0126), which increased type I collagen mRNA in MC3T3-E1 cells, indicating that the inhibition of ERK pathway upregulates type I collagen gene expression. Low serum (0.3%) markedly increased type I collagen mRNA. MEK inhibitor PD inhibited c-fos induction by FGF-2 and PDGF-BB, suggesting that c-fos is the downstream target of ERK pathway. Our data have clearly demonstrated for the first time that the ERK MAPK pathway play an important role in the regulation of type I collagen gene expression in osteoblastic cells. Results also showed that one of the mechanisms by which FGF-2 and PDGF-BB downregulate type I collagen gene expression in the osteoblast is through the activation of ERK signaling pathway.
3T3 Cells↗
Expression of human hyaluronan synthases in response to external stimuli.
In the present study we have investigated the expression of mRNAs for hyaluronan synthase isoforms (HAS1, HAS2 and HAS3) in different cells in response to various stimuli. Human mesothelial cells, which synthesize large amounts of hyaluronan, express mRNAs encoding all three HAS isoforms, whereas their transformed counterparts, mesothelioma cells, which produce only minute amounts of hyaluronan, express only HAS3 mRNA. Human lung fibroblasts and the glioma cell line U-118 MG express only the HAS2 and HAS3 genes. The expression of the transcripts was higher in subconfluent than in confluent cultures and was well correlated with the production of hyaluronan by the cells. Stimulation of mesothelial cells with platelet-derived growth factor-BB induced an up-regulation of mRNA for HAS2 to a maximum after 6 h of stimulation; HAS1 and HAS3 genes were only induced slightly. Transforming growth factor-beta1 reduced HAS2 mRNA slightly, and hydrocortisone reduced it strongly, within 6 h of stimulation in mesothelial cell cultures but did not significantly affect the expression of mRNAs for HAS1 and HAS3. Induction of HAS1 and HAS2 protein levels in response to the stimuli above correlated with HAS transcript levels. Thus the expression of the three HAS isoforms is more prominent in growing cells than in resting cells and is differentially regulated by various stimuli suggesting distinct functional roles of the three proteins.
Anti-Inflammatory Agents↗
[Growth factor for diabetic foot ulcer. How man amputations are preventable].
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Amputation, Surgical↗
Differential TPA and PDGF-BB effects on subcellular localisation of PKC alpha and beta I in C3H/10T1/2 cells.
60-75% of PKC alpha and 30-40% of PKC beta I++ protein was located to the membranes and nuclear/nuclear associated endoplasmatic reticulum fractions of resting 10T1/2CI 8 mouse embryo fibroblasts. On average, 35% of the PKC alpha and 65% of the PKC beta I++ isoforms existed in a soluble state. Maximum PDGF-BB-mediated Erk1 activation was obtained without significant changes in soluble PKC alpha- or PKC beta I++- levels. The subcellular localisation of PKC alpha and PKC beta I was not affected by PDGF-BB treatment. 12-O-tetradecanoyl phorbol-13-acetate (TPA) caused translocation of cytoplasmic PKC alpha and beta I to the nucleus/nuclear associated endoplasmatic reticulum fraction. Down-regulation of PKC and bisindolylmaleimide I inhibited both TPA and PDGF-BB stimulated Erk1 activity. We are the first to show that PDGF-mediated activation of Erk1 involves a PKC-dependent step in 10T1/2CI 8 cells. We also provide novel evidence that PDGF-BB mediated Erk1 activation can take place in these cells without apparent recruitment of soluble PKC alpha/beta I to the particulate cell fractions.
Animals↗
Expression regulation of hyaluronan synthase in corneal endothelial cells.
PURPOSE: Our previous study showed that hyaluronan synthase (HAS), the enzyme protein of hyaluronan (HA) biosynthesis, is expressed in ocular tissues including the corneal endothelium. In the current study, the mechanism that regulates HAS expression in bovine corneal endothelial cells (BCECs) was investigated. METHODS: Cultured BCECs were used. HAS expression in BCECs at the mRNA level was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis. The effects of transforming growth factor (TGF)-beta and platelet-derived growth factor (PDGF)-BB on HAS expression were examined by quantitative RT-PCR. The involvement of the Smad family (intracellular signal transducer of TGF-beta) was also investigated. The expression of HAS in BCECs at the protein level was confirmed by immunocytochemistry and Western blot analysis. RESULTS: Three HAS isoforms in BCECs were expressed at the mRNA level. The transcriptional sizes of each HAS in BCECs were 4.9 kb for HAS1, 2.8 kb for HAS2, and 1.6 kb for HAS3. The expression of HAS2 at the mRNA level was stimulated by TGF-beta1 and/or PDGF-BB treatment. In contrast, HAS1 and HAS3 expression was not affected by these growth factors. The additive effects of TGF-beta1 and PDGF-BB were observed in the stimulation of the expression levels of HAS2. HAS2 upregulation by these growth factors was also detected by Western blot analysis. The stimulation of the expression of HAS2 at the mRNA level by TGF-beta was accelerated by the overexpression of Smad2, Smad3, and Smad4 and inhibited by that of Smad7, all of which were confirmed to be involved in the signal transduction from TGF-beta through HAS expression. CONCLUSIONS: Although three HAS isoforms were expressed in the corneal endothelial cells, the expression of HAS2 was upregulated by TGF-beta1 and/or PDGF-BB. HAS2 expression was regulated by TGF-beta through Smad family members.
Amino Acid Sequence↗
Enhanced wound healing using topical recombinant human platelet-derived growth factor.
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Anticoagulants↗
Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis.
Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and the complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibroblasts, which express high amounts of TF, were studied. Fibroblasts incubated with FVIIa migrated toward a concentration gradient of PDGF-BB at approximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the increase in chemotaxis induced by FVIIa/TF. Moreover, a pronounced suppression of chemotaxis induced by PDGF-BB was observed with active site-inhibited FVIIa (FFR-FVIIa). The possibility that hyperchemotaxis was induced by a putative generation of FXa and thrombin activity was excluded. FVIIa/TF did not induce increased levels of PDGF beta-receptors on the cell surface. Thus, the hyperchemotaxis was not a result of this mechanism. FVIIa induced the production of inositol-1,4, 5-trisphosphate to the same extent as PDGF-BB; the effects of FVIIa and PDGF-BB were additive. FFR-FVIIa did not induce any release of inositol-1,4,5,-trisphosphate. Thus, binding of catalytically active FVIIa to TF can, independent of coagulation, modulate cellular responses, such as chemotaxis.
Amino Acid Chloromethyl Ketones↗
The inducible cAMP early repressor ICERIIgamma inhibits CREB and AP-1 transcription but not AT1 receptor gene expression in vascular smooth muscle cells.
Growth factors and agonists of both G alpha s and G alpha q-coupled receptor agonists each down regulate angiotensin AT1 receptor gene expression in vascular smooth muscle cells. To test whether the transcription factor CREB is in the pathway involved in modulation of AT1-receptor gene expression, AT1 receptor mRNA levels were measured after stimulation with forskolin, angiotensin II and PDGF-BB in VSMC expressing the inducible cAMP early repressor protein, ICERIIgamma, fused to the green fluorescent protein (eGFP). This fusion protein inhibits luciferase induction from promoters driven by either CREB response elements (CRE) or, unexpectedly, by tetradecanoylphorbol acetate response elements (TRE), which bind activator protein (AP-1). EGFP-ICERIIgamma expression inhibits occupancy of CRE and TRE elements by endogenous VSMC nuclear proteins. Nevertheless, agonist-induced AT1-receptor mRNA down regulation is unaffected by eGFP-ICERIIgamma expression. Although CREB transcription is activated by multiple classes of agonists in VSMC, and ICER can inhibit agonist-induced transcription mediated by both CREB and AP-1 enhancers, these transcription factors are not obligate components of the pathways regulating AT1-R gene expression in rat VSMC.
Angiotensin II↗
The cell survival signal Akt is differentially activated by PDGF-BB, EGF, and FGF-2 in osteoblastic cells.
Stimulation of osteoblast survival signals may be an important mechanism of regulating bone anabolism. Protein kinase B (PKB/Akt), a serine-threonine protein kinase, is a critical regulator of normal cell growth, cell cycle progression, and cell survival. In this study we have investigated the signaling pathways activated by growth factors PDGF-BB, EGF, and FGF-2 and determined whether PDGF-BB, EGF, and FGF-2 activated Akt in human or mouse osteoblastic cells. The results demonstrated that both ERK1 and ERK2 were activated by FGF-2 and PDGF-BB. Activation of ERK1 and ERK2 by PDGF-BB and FGF-2 was inhibited by PD 098059 (100 microM), a specific inhibitor of MEK. Wortmannin (500 nM), a specific inhibitor of phosphatidylinositol 3-kinase ( PI 3-K), inhibited the activation of ERK1 and ERK2 by PDGF-BB but not by FGF-2 suggesting that PI 3-K mediated the activation of ERK MAPK pathway by PDGF-BB but not by FGF-2. Rapamycin, an inhibitor of p70 S6 protein kinase and a downstream target of ERK1/2 and PI 3-K, did not affect the activation of ERK1 and ERK2 by the growth factors. Furthermore, our results demonstrated that Akt, a downstream target of PI 3-K, was activated by PDGF-BB but not by FGF-2. Akt activation by PDGF-BB was inhibited by PI 3-kinase inhibitor LY294002. Rapamycin had no effect on Akt activation. Epidermal growth factor (EGF) also activated Akt in osteoblastic cells which was inhibited by LY294002 but not by rapamycin. Taken together, our data for the first time revealed that the activation of ERK1/2 by PDGF-BB is mediated by PI 3-K, and secondly, Akt is activated by PDGF-BB and EGF but not by FGF-2 in human and mouse osteoblastic cells. These results are of critical importance in understanding the role of these growth factors in apoptosis and cell survival. PDGF-BB and EGF but not FGF-2 may stimulate osteoblast cell survival.
3T3 Cells↗
Platelet-derived growth factor stimulated vascular smooth muscle cell proliferation and its molecular mechanism.
AIM: To study the molecular mechanism of platelet-derived growth factor (PDGF)-BB-stimulated vascular smooth muscle cell (VSMC) proliferation. METHODS: DNA synthesis was measured by [3H]thymidine incorporation. Phosphorylation of the 42- and 44-kDa Ca(2+)-calmodulin dependent protein kinase (CCDPK) was measured by Western blotting method. The expression of c-myc specific mRNA was detected by in situ hybridization. RESULTS: PDGF-BB (2 micrograms.L-1) induced DNA synthesis and activated CCDPK in a concentration-dependent manner and a induced a marked c-myc mRNA expression. Egtazic acid (EGTA, 5 mmol.L-1), genistein (400 mumol.L-1) or PD 98059 (50 mumol.L-1) reduced PDGF-BB (2 micrograms.L-1)-induced CCDPK activities and inhibited VSMC [3H]thymidine incorporation (P < 0.05). PD 98059 (50 mumol.L-1) also inhibited PDGF-BB (2 micrograms.L-1)-induced c-myc mRNA expression. CONCLUSION: PDGF stimulated VSMC proliferation by activation of p44/p42 CCDPK, which is mediated by Ca2+ and protein tyrosine kinase (PTK), and up-regulation of c-myc mRNA expression.
Animals↗
PDGF-induced coupling of function with metabolism in microvascular pericytes of the retina.
PURPOSE: The aim of this study was to test the hypothesis that platelet-derived growth factor (PDGF)-BB regulates the physiology of retinal pericytes, which are contractile cells located on the abluminal surface of capillaries. The expression of PDGF-BB and its cognate receptor in retinal vessels suggests a vasoactive function. However, although endothelium-derived PDGF-BB appears vital for the development of pericyte-containing microvessels, its role in the mature vasculature remains uncertain. METHODS: Based on the premise that ion channels mediate the responses of pericytes to vasoactive signals, the perforated-patch configuration of the patch-clamp technique was used to determine the effect of PDGF-BB on the ionic currents and membrane potential of pericytes located on microvessels freshly isolated from the adult rat retina. Changes in pericyte calcium levels were monitored with the calcium indicator fluo-4. Differential interference contrast optics and image analysis software aided in assessing the effects of PDGF-BB on the lumens of isolated pericyte-containing microvessels. In some experiments, blockers of adenosine triphosphate (ATP) synthesis created chemical ischemia. RESULTS: Electrophysiological recordings from pericytes showed that PDGF-BB can activate nonspecific cation channels, chloride channels, and ATP-sensitive potassium channels. The metabolic status of an isolated capillary determined which of these ion channels were activated by PDGF-BB and thereby whether the membrane potential decreased or increased, the cell calcium rose or fell, and the vessel lumen constricted or dilated. CONCLUSIONS: The ability of PDGF-BB to be a vasoconstrictor when energy supplies are ample and to be a vasodilator under ischemic conditions may provide an efficient mechanism to link capillary function to local metabolic needs.
Aniline Compounds↗
[Expression of cyclin dependent kinase inhibitor p27 during proliferation in vascular smooth muscle cell].
This study was to investigate cell cycle distribution of the vascular smooth muscle cells (VSMCs) and negative regulator of cell proliferation p27 expression caused by platelet derived growth factor BB (PDGF-BB), angiotensin II (Ang II) and arginine vasopressin (AVP). Deprived of fotal calf serum for 48 h, cultured VSMCs in quiescent condition were collected at different times after stimulation of Ang II, AVP and PDGF-BB. Cell cycle distribution and p27 expression were determined with a flow cytometer. The results showed that the protein content of VSMCs was significantly increased (43.6%) by Ang II as a result of hypertrophy, but Ang II did not lead to downregulation of p27. AVP could downregulate p27 slightly. PDGF could inhibit p27 expression significantly and cause VSMCs hyperplasia. These results suggest that the progression of VSMCs through G1 to S phase might be brought out by the inhibition of p27 during proliferation.
Angiotensin II↗
Adenovirus-mediated expression of a truncated PDGFbeta receptor inhibits thrombosis and neointima formation in an avian arterial injury model.
Platelet-derived growth factor (PDGF) is a major mediator of neointima formation after arterial injury. We constructed a recombinant adenovirus, Ad/PDGFtr, that expresses the soluble extracellular domain of the murine PDGFbeta receptor (PDGFtr). The expressed PDGFtr was appropriately glycosylated and secreted by chicken vascular smooth muscle cells (SMCs) in vitro. The expressed PDGFtr inhibited human PDGF-BB induced receptor autophosphorylation, and also inhibited PDGF-BB induced cell proliferation without affecting PDGF-AA induced mitogenesis. In vivo transduction of balloon-injured rooster femoral arteries with Ad/PDGFtr resulted in expression and secretion of the glycosylated PDGFtr. The expressed PDGFtr significantly inhibited neointima formation compared with controls. Neointima-associated thrombus was significantly reduced in Ad/PDGFtr transduced arteries compared with controls. Thus, in addition to impacting on SMC proliferation and migration, PDGF-BB plays a role in thrombus formation in response to arterial injury. Growth factor inhibition by localized gene delivery constitutes a powerful approach to intervene in the molecular pathways involved in vascular disease.
Animals↗
[Effects of intralesional injection of kenalog or interferon alpha-2b on PDGF BB gene expression in situ of hypertrophic scars].
OBJECTIVE: The study is to determine whether kenalog or interferon alpha-2b inhibits fibroblast growth in hypertrophic scars through decreasing PDGF. METHOD: Six patients with hypertrophic scars received intralesional injection of kenalog or interferon alpha-2b. On the 3rd and 7th day after injection, scar samples from each patient were collected and PDGF mRNA expressions in situ were studied. RESULTS: 1. On the 7th day after intralesional injection of kenalog or interferon alpha-2b, expressions of PDGF BB mRNAs decreased significantly (P < 0.01). However, on the 3rd day the expressions of PDGF BB mRNAs of the intralesional-injected area and non-injected area were not significantly different (P > 0.05). 2. Gene expressions of PDGF BB in situ were higher in hypertrophic scars than in normal skin. CONCLUSION: The mechanism of kenalog or interferon alpha-2b in ameliorating hypertrophic scar is to reduce mitosis and prohibit proliferation of fibroblasts in hypertrophic scars by inhibiting PDGF gene expression.
Adolescent↗