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PubMed2000

Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity.

Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([(3)H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor-induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological (10(-9) mol/L) concentrations of 17beta-estradiol and low concentrations (10(-8) to 10(-7) mol/L) of 17beta-estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17alpha-estradiol, or estrone sulfate. The inhibitory effects of 17beta-estradiol and other inhibitory estrogens were completely reversed by 100 micromol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.

Aorta↗
PubMed2000

Matrix metalloproteinase and alphavbeta3 integrin-dependent vascular smooth muscle cell invasion through a type I collagen lattice.

Smooth muscle cell (SMC) migration from the tunica media to the intima is a key event in the development of atherosclerotic lesions and in restenosis after angioplasty. SMCs require not only migratory but also degradative abilities that enable them to migrate through extracellular matrix proteins, which surround and embed these cells. We used a collagen type I lattice as a coating on top of a porous filter as a matrix barrier in a chamber to test the invasive behavior of SMCs in response to a chemoattractant (invasion assay) and compared that behavior with simple SMC migration through collagen type I-coated filters (migration assay). Inhibitors of matrix metalloproteinase, KB-R8301, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), TIMP-2, and peptide 74, attenuated platelet-derived growth factor-BB (PDGF-BB)-directed SMC invasion across the collagen lattice, whereas no effect was seen with these inhibitors on simple SMC migration through collagen-coated filters. RGD peptide inhibited SMC invasion but did not affect SMC migration. Anti-alphavbeta3 integrin antibody attenuated PDGF-BB-directed SMC invasion, whereas other antibodies against RGD-recognizing integrins, namely alphavbeta5 and alpha5, had no effect. None of these antibodies had any effect on simple SMC migration. RGD peptide and anti-alphavbeta3 antibody inhibited the attachment and spreading of SMCs on denatured collagen but not on native collagen. These findings indicate that there is a difference in the mechanisms between simple SMC migration across a collagen-coated filter and SMC invasion through a fibrillar collagen barrier. A proteolytic process is required for SMC invasion, and the degradation of matrix proteins alters the relationship between matrix protein molecules and SMC surface integrins.

Animals↗
PubMed2000

Intracellular Ca(2+) handling in vascular smooth muscle cells is affected by proliferation.

Despite intensive interest in the dedifferentiation process of vascular smooth muscle cells, very little data are available on intracellular Ca(2+) signaling. The present study was designed to investigate the evolution of the intracellular Ca(2+) pools when rat aortic smooth muscle cells (RASMCs) proliferate and to define the mechanisms involved in the functional alterations. RASMCs were cultured in different conditions, and [Ca(2+)](i) was measured by use of fura 2. Expression of the sarco(endo)plasmic reticulum Ca(2+) pumps (SERCA2a and SERCA2b), Ca(2+) channels, the ryanodine receptor (RyR), and the inositol trisphosphate receptor (IP3R) was studied by reverse transcription-polymerase chain reaction and immunofluorescence. Antibodies specific for myosin heavy chain isoforms were used as indicators of the differentiation state of the cell, whereas an anti-proliferating cell nuclear antigen antibody was a marker of proliferation. SERCA2a, SERCA2b, RyR3, and IP3R-1 mainly were present in the aorta in situ and in freshly isolated RASMCs. These cells used the 2 types of Ca(2+) channels to release Ca(2+) from a common thapsigargin-sensitive store. Proliferation of RASMCs, induced by serum or by platelet-derived growth factor-BB, resulted in the disappearance of RyR and SERCA2a mRNAs and proteins and in the loss of the caffeine- and ryanodine-sensitive pool. The differentiated nonproliferative phenotype was maintained in low serum or in cells cultured at high density. In these conditions, RyR and SERCA2a were also present in RASMCs. Thus, expression of RyR and SERCA2a is repressed by cell proliferation, inducing loss of the corresponding Ca(2+) pool. In arterial smooth muscle, Ca(2+) release through RyRs is involved in vasodilation, and suppression of the ryanodine-sensitive pool might thus alter the control of vascular tone.

Animals↗
PubMed2000

Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin.

This study tests the hypothesis that alpha(v)beta(3) integrin receptors play a critical role in smooth muscle cell (SMC) migration after arterial injury and facilitate migration through the upregulation of matrix metalloproteinase (MMP) activity. We showed that beta(3) integrin mRNA was upregulated by SMCs in the balloon-injured rat carotid artery in coincidence with MMP-1 expression and early SMC migration. Treatment with the beta(3) integrin-blocking antibody F11 significantly decreased SMC migration into the intima at 4 days after injury, from 110.8+/-30.8 cells/mm(2) in control rats to 10.29+/-7.03 cells/mm(2) in F11-treated rats (P=0.008). By contrast, there was no effect on medial SMC proliferation or on medial SMC number in the carotid artery at 4 days. In vitro, we found that human newborn SMCs produced MMP-1 but that adult SMCs did not. This was possibly due to the fact that newborn SMCs expressed alpha(v)beta(3) integrin receptors, whereas adult SMCs did not. Stimulation of newborn (alpha(v)beta(3)+) SMCs with osteopontin, a matrix ligand for alpha(v)beta(3), increased MMP-1 production from 114.4+/-35.8 ng/mL at 0 nmol/L osteopontin to 232.5+/-57.5 ng/mL at 100 nmol/L osteopontin. Finally, we showed that stimulation of newborn SMCs with platelet-derived growth factor-BB and osteopontin together increased the SMC production of MMP-9. Thus, our results support the hypothesis that SMC alpha(v)beta(3) integrin receptors play an important role in regulating migration by stimulating SMC MMP production.

Animals↗
PubMed2002

Red wine polyphenols inhibit vascular smooth muscle cell migration through two distinct signaling pathways.

BACKGROUND: Red wine polyphenols (RWPs) have been shown to have an antiatherogenic activity mainly through antioxidative effects on LDL oxidation. Although vascular smooth muscle cell (SMC) migration is critical to atherosclerosis formation, the effect of RWPs on SMC migration has not been elucidated. In this study, we investigated whether RWPs could affect the migration of cultured SMCs stimulated by growth factors. METHODS AND RESULTS: RWP concentration dependently inhibited platelet-derived growth factor (PDGF)-BB-induced and serum-induced SMC migration in wounding assay and Boyden chamber assay. However, these inhibitory effects of RWPs were not seen in serum-stimulated vascular endothelial cell migration in either assay. Moreover, specific inhibitors of phosphatidylinositol-3' kinase (PI3K) and p38 mitogen-activated protein kinase (p38(MAPK)), but not of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), reduced PDGF-BB-induced SMC migration. To elucidate the signaling mechanism underlying the RWP effects, we investigated the effects of RWPs on the activity of PI3K and the phosphorylation of MAPK pathways in PDGF-BB-stimulated SMCs. RWPs inhibited the PI3K activity and p38(MAPK) phosphorylation, but not ERK1/2 phosphorylation, in a concentration-dependent manner. Moreover, the phosphorylation of MKK3/6, an upstream kinase of p38(MAPK), was also inhibited by RWP treatment in a concentration-dependent manner, suggesting that the inhibitory effect of RWPs on the p38(MAPK) pathway works upstream of MKK3/6. The concentration-effect relationship of RWPs necessary for the inhibition of PI3K and p38(MAPK) pathways was similar to that of cell migration assays. CONCLUSIONS: RWPs inhibit the SMC migration through the inhibition of 2 distinct signaling pathways and thus exert antiatherogenic actions.

Animals↗
PubMed2002

Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell.

BACKGROUND: Vascular smooth muscle cell proliferation plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the human injured artery and suppressed endothelial inflammatory response as well as macrophage-to-foam cell transformation. The present study investigated the effects of adiponectin on proliferation and migration of human aortic smooth muscle cells (HASMCs). Methods and Results- HASMC proliferation was estimated by [(3)H] thymidine uptake and cell number. Cell migration assay was performed using a Boyden chamber. Physiological concentrations of adiponectin significantly suppressed both proliferation and migration of HASMCs stimulated with platelet-derived growth factor (PDGF)-BB. Adiponectin specifically bound to (125)I-PDGF-BB and significantly inhibited the association of (125)I-PDGF-BB with HASMCs, but no effects were observed on the binding of (125)I-PDGF-AA or (125)I-heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) to HASMCs. Adiponectin strongly and dose-dependently suppressed PDGF-BB-induced p42/44 extracellular signal-related kinase (ERK) phosphorylation and PDGF beta-receptor autophosphorylation analyzed by immunoblot. Adiponectin also reduced PDGF-AA-stimulated or HB-EGF-stimulated ERK phosphorylation in a dose-dependent manner without affecting autophosphorylation of PDGF alpha-receptor or EGF receptor. CONCLUSIONS: The adipocyte-derived plasma protein adiponectin strongly suppressed HASMC proliferation and migration through direct binding with PDGF-BB and generally inhibited growth factor-stimulated ERK signal in HASMCs, suggesting that adiponectin acts as a modulator for vascular remodeling.

Adipocytes↗
PubMed2002

Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells.

BACKGROUND: Smooth muscle cell (SMC) accumulation in the intima of vessels is a key event in the pathogenesis of transplant atherosclerosis. The traditional hypothesis that SMCs in the lesion are derived from the media of the donor vessel has been challenged by recent observations, but the cell origin is still not well established. METHODS AND RESULTS: Here, we use a simplified model of artery allografts in transgenic mice to clearly identify the source of SMCs in transplant atherosclerosis. Aortic segments donated by BALB/c mice allografted to ROSA26 (C57B/6) mice expressing beta-galactosidase (gal) in all tissues showed that neointimal cells derived exclusively from host cells. It was also demonstrated that SMCs of neointimal and atherosclerotic lesions in vessels allografted to mice expressing beta-gal only in SMCs (SM-LacZ) or to apoE-deficient/SM-LacZ mice originated from the recipient, and not donor vessels. Interestingly, bone marrow transplantation of SM-LacZ beta-gal-expressing cells into aortic allograft recipients revealed completely negative beta-gal staining of neointimal and atherosclerotic lesions. However, a population of beta-gal-positive cells in lesions of allografts was observed in chimeric mice with ROSA26 beta-gal-expressing marrow cells. When bone marrow cells from both ROSA26 and SM-LacZ mice were cultured and stimulated with platelet-derived growth factor-BB, alpha-actin and beta-gal double-positive cells were found, suggesting that bone marrow cells have an ability to differentiate into SMCs. CONCLUSIONS: Thus, we provide strong evidence that SMCs of neointimal and atherosclerotic lesions in allografts are derived from the recipients and that non-bone marrow-derived progenitor cells are a possible source of SMCs in atherosclerotic lesions.

Actins↗
PubMed2003

Inhibitory activity of clinical thiazolidinedione peroxisome proliferator activating receptor-gamma ligands toward internal mammary artery, radial artery, and saphenous vein smooth muscle cell proliferation.

BACKGROUND: The proliferation of vascular smooth muscle cells (VSMCs) is a known response to arterial injury that is an important part of the process of restenosis and atherosclerosis. People with diabetes have an increased risk of cardiovascular disease resulting from accelerated coronary atherosclerosis. The newest drugs for Type 2 diabetes are thiazolidinediones, which are insulin-sensitizing peroxisome proliferator activating receptor-gamma (PPARgamma) ligands. We investigated the antiproliferative effects of troglitazone, rosiglitazone, and pioglitazone on VSMCs derived from the three vascular beds used for coronary artery by-pass grafting: the internal mammary and radial artery and saphenous veins. METHODS AND RESULTS: The three vessels yielded proliferating cells of slightly differing morphology. Inhibition of cell proliferation was assessed by cell counting and cell cycle studies by Western blotting for phosphorylated retinoblastoma protein. All three thiazolidinediones showed inhibitory potency toward cell proliferation with a potency troglitazone>rosiglitazone approximately pioglitazone, and this potency profile was maintained toward the growth factor and insulin-stimulated phosphorylation of the retinoblastoma protein, which controls cell cycle progression. CONCLUSIONS: The inhibitory potency of clinical thiazolidinediones toward different vascular sources is dependent on the individual thiazolidinedione and very little on the vascular source.

Becaplermin↗
PubMed2003

Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells.

BACKGROUND: The coordinated activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non-heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs). METHODS AND RESULTS: We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase-polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo. CONCLUSIONS: Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.

Animals↗
PubMed1999

Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor. However, its mitogenic effects on vascular smooth muscle cells (SMCs) remain controversial. We investigated the role of ET-1 in human SMC growth and its synergistic effect with platelet-derived growth factor (PDGF). METHODS AND RESULTS: Human aortic SMCs were cultured and cell proliferation was assayed by [3H]thymidine incorporation. PDGF receptor expression, activation of mitogen-activated protein kinase (MAPK), cell cycle regulators such as cyclin-dependent kinase 2 (Cdk2), Cdk inhibitor (p27(Kip1)), and retinoblastoma protein (pRb) were analyzed by immunoblotting. ET-1 on its own was unable to stimulate [3H]thymidine incorporation but dramatically potentiated the effect of PDGF-BB up to 6-fold (P<0.001). Most of the potentiating effects (88%) were blocked by the ETA receptor antagonist LU135252 and slightly further blocked by the ETA/B receptor antagonist bosentan (P<0.05). ET-1 stimulated MAPK, but it neither potentiated PDGF-induced MAPK activation nor overexpressed PDGF receptors. In contrast to PDGF-BB, ET-1 had no regulatory effects on Cdk2, p27(Kip1), and pRb. CONCLUSIONS: In human SMCs, ET-1 activates MAPK but has no mitogenic effects on its own. However, ET-1 markedly potentiates proliferation to PDGF, mainly via ETA receptors. This may represent an important function of ET-1 for vascular structural changes in patients and provide new therapeutic opportunities for ET-1 receptor antagonists.

Aorta↗
PubMed2001

Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells.

BACKGROUND: Previous investigations provide evidence that an enzyme related to the phagocyte NADPH oxidase produces superoxide in the blood vessel wall. These data, however, are confounded by observations that both NADPH and NADH serve as substrates for superoxide production in vascular cells. To clarify this issue, we compared the superoxide-generating capabilities of vascular smooth muscle cells (VSMCs) derived from wild-type (p47phox(+/+); phagocyte oxidase) mice with those from mice that lack p47phox (p47phox(-/-); "knockout"), an essential component of the phagocyte NADPH oxidase. METHODS AND RESULTS: VSMCs were derived from aortic explants harvested from p47phox(+/+) or p47phox(-/-) mice. VSMCs from p47phox(+/+) but not those from p47phox(-/-) mice produced superoxide after stimulation by phorbol myristate acetate. Consistent with this, p47phox was detected only in p47phox(+/+) VSMCs. p47phox-transduced p47phox(-/-) but not enhanced green fluorescent protein-transduced p47phox(-/-) VSMCs generated significant levels of superoxide after stimulation by angiotensin II or platelet-derived growth factor-BB (PDGF-BB). Enhanced expression of recombinant p47phox in p47phox-transduced p47phox(-/-) cells correlated with superoxide production in these cells. CONCLUSIONS: These data provide direct functional proof that an oxidase requiring the p47phox component mediates superoxide release from VSMCs in the blood vessel wall in response to angiotensin II or PDGF-BB.

Actins↗
PubMed1994

Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only.

BACKGROUND: Hypoxia and indirect angiogenic factors may stimulate angiogenesis via induction of endothelial cell mitogen(s). To evaluate this hypothesis, we investigated whether low oxygen tension or cytokines known to promote neovascularization in vivo could modulate the expression of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in human vascular smooth muscle cells (SMCs). METHODS AND RESULTS: SMCs were treated with platelet-derived growth factor BB (PDGF-BB) or transforming growth factor-beta 1 (TGF-beta 1) or exposed to low oxygen tension in serum-free medium. Northern analysis detected low basal levels of VEGF and bFGF mRNA in extracts of unstimulated SMCs. However, both VEGF and bFGF transcripts increased after administration of PDGF-BB (10 or 20 ng/mL) or TGF-beta 1 (0.1 to 10 ng/mL). Hypoxia was a potent stimulus for VEGF gene expression but had no apparent effect on bFGF steady-state mRNA levels. CONCLUSIONS: These results indicate that certain indirect angiogenic cytokines, such as PDGF-BB or TGF-beta 1, may act via induction of bFGF and VEGF gene expression in cells resident near endothelial cells in vivo. Hypoxia constitutes a potent stimulus for VEGF gene expresion but does not regulate bFGF under the same experimental conditions.

Becaplermin↗
PubMed1995

Failure of heparin to inhibit intimal hyperplasia in injured baboon arteries. The role of heparin-sensitive and -insensitive pathways in the stimulation of smooth muscle cell migration and proliferation.

BACKGROUND: Heparin is a potent inhibitor of smooth muscle cell (SMC) growth and intimal hyperplasia in animal models but has been ineffective in inhibiting restenosis in humans. This difference may relate to flaws in clinical study design or, alternatively, to interspecies differences in SMC response to heparin. To determine whether heparin could inhibit intimal hyperplasia in a species more closely related to humans, we studied the effect of a low-molecular-weight heparin (LMWH) on baboon SMC proliferation and migration in culture and in arteries subjected to experimental angioplasty. METHODS AND RESULTS: LMWH or saline was infused continuously after experimental angioplasty of baboon peripheral arteries (six animals per group). After 28 days, bromodeoxyuridine (BrdU) was given to label proliferating cells, and balloon-injured arteries were perfusion-fixed in situ and removed for analysis. All arteries had reendothelialized (Evans blue dye exclusion). LMWH increased partial thromboplastin time (LMWH, 81.7 +/- 8.4 seconds versus saline, 34.7 +/- 0.8 seconds [mean +/- SEM]; P = .004) but failed to inhibit intimal thickening or SMC proliferation (intimal area: LMWH, 0.19 +/- 0.03 mm2 versus saline, 0.21 +/- 0.03 mm2; BrdU labeling: LMWH, 2.9 +/- 0.6% versus saline, 2.4 +/- 0.4%; P = NS). In culture, LMWH and standard heparin (100 micrograms/mL) significantly inhibited serum-induced but not platelet-derived growth factor (PDGF-BB)-induced SMC proliferation (% control, serum: LMWH, 60.5 +/- 4.0%, P = .0002; standard heparin, 29.4 +/- 8.2%, P = .0001; % control, PDGF-BB: LMWH, 117.7 +/- 11.3%, P = NS; standard heparin, 90.9 +/- 14.4%, P = NS) and SMC migration (% control, serum: LMWH, 15.3 +/- 1.9%, P = .0198; standard heparin, 26.4 +/- 13.8%, P = .0032; % control, PDGF-BB: LMWH, 98.5 +/- 14.3%, P = NS; standard heparin, 100.0 +/- 13.5%, P = NS). CONCLUSIONS: LMWH failed to inhibit intimal hyperplasia in a baboon angioplasty model. Furthermore, LMWH blocked serum-induced but not PDGF-BB-induced SMC proliferation and migration in culture. Thus, heparin-sensitive and -insensitive pathways exist for SMC activation. The relative importance of each pathway induced by injury may vary between species and thus account for different responses to heparin.

Animals↗
PubMed1997

Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells.

BACKGROUND: Platelet-derived growth factor (PDGF) and superoxide anion (O2.-) have been implicated in vascular diseases. We investigated whether PDGF stimulates the production of O2.- in human aortic smooth muscle cells (HSMCs) and whether O2.- leads in this way to the activation of nuclear factor-kappaB (NF-kappaB) and induction of monocyte chemoattractant protein 1 (MCP-1) in PDGF-stimulated HSMCs. METHODS AND RESULTS: PDGF-AB concentration- and time-dependently stimulated O2.- generation from HSMCs. The stimulatory effect of PDGF-AB was mimicked by PDGF-BB but not by PDGF-AA. The generation of O2.- by PDGF-AB was attenuated by the NAD(P)H oxidase inhibitor iodonium diphenyl, the specific protein kinase C (PKC) inhibitor Ro 31-8220, and the phosphatidylinositol 3-kinase inhibitor wortmannin. Allopurinol and nifedipine had no effect on PDGF-AB-induced O2.- release, whereas indomethacin potentiated this response. Gel mobility shift assay revealed that PDGF-AB increased the binding activity of NF-kappaB, which contained predominantly the p50/p65 heterodimer in nuclear extracts from HSMCs. Superoxide dismutase as well as iodonium diphenyl, Ro 31-8220, and wortmannin attenuated PDGF-AB-induced activation of NF-kappaB and expression of MCP-1 mRNA. In contrast, superoxide dismutase did not inhibit the interleukin-1beta-induced NF-kappaB activation. CONCLUSIONS: The results demonstrate that PDGF stimulates O2.- generation in HSMCs via PKC-dependent and wortmannin-sensitive pathways involving flavoenzyme(s). This PDGF-induced O2.- production may be involved in vascular lesion formation by mediating, at least in part, NF-kappaB activation and MCP-1 induction.

Allopurinol↗
PubMed1998

Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration.

BACKGROUND: The objectives of the present study were (1) to determine whether lysophosphatidylcholine (lyso-PC), a prominent component of oxidatively modified LDL, induces migration of human coronary artery smooth muscle cells (SMCs) and, if so, to clarify the mechanism, and (2) to investigate the possible interactions of lyso-PC and platelet-derived growth factor (PDGF)-BB, endothelin- (ET-1), adrenomedullin (AM), or vitamin E on SMC migration by the Boyden's chamber method. METHODS AND RESULTS: Lyso-PC induced SMC migration in a concentration-dependent manner between 10(-6) and 5 x 10(-5) mol/L. By contrast, phosphatidylcholine was without significant activity, and lysophosphatidylinositol and lysophosphatidylserine were much less effective than lyso-PC. Lyso-PC increased basic fibroblast growth factor (bFGF) production in a concentration-dependent manner between 10(-6) and 5 x 10(-5) mol/L in these cells. Furthermore, lyso-PC-induced SMC migration was inhibited by neutralizing antibody to bFGF but not by neutralizing antibody to transforming growth factor-beta1. Lyso-PC-induced migration was significantly enhanced by PDGF-BB or ET-1 but was clearly inhibited by human AM and vitamin E. CONCLUSIONS: These results indicate that (1) lyso-PC induces human coronary artery SMC migration at least in part through release of endogenous bFGF and (2) this lyso-PC-induced migration can be further induced by PDGF-BB and ET-1 and can be inhibited by human AM and vitamin E. Lyso-PC may recruit medial SMCs during the process of coronary atherosclerosis in part by releasing bFGF in concert with PDGF-BB or ET-1 in vascular tissues. This lyso-PC-induced SMC migration may be suppressed by AM and vitamin E under certain pathological conditions.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Antioxidants improve impaired insulin-mediated glucose uptake and prevent migration and proliferation of cultured rabbit coronary smooth muscle cells induced by high glucose.

BACKGROUND: To explore the role of intracellular oxidative stress in high glucose-induced atherogenesis, we examined the effect of probucol and/or alpha-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Chronic high-glucose-medium (22. 2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, [3H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/L+16.6 mmol/L mannose). Probucol and alpha-tocopherol significantly suppressed high glucose-induced increase in VSMC migration, cell number, and [3H]thymidine incorporation. Probucol and alpha-tocopherol suppressed high glucose-induced elevation of the cytosolic ratio of NADH/NAD+, phospholipase D, and membrane-bound protein kinase C activation. Probucol, alpha-tocopherol, and calphostin C improved the high glucose-induced suppression of insulin-mediated [3H]deoxyglucose uptake. Chronic high-glucose treatment increased the oxidative stress, which was significantly suppressed by probucol, alpha-tocopherol, suramin, and calphostin C. CONCLUSIONS: These findings suggest that probucol and alpha-tocopherol may suppress high glucose-induced VSMC migration and proliferation via suppression of increases in the cytosolic ratio of free NADH/NAD+, phospholipase D, and protein kinase C activation induced by high glucose, which result in reduction in intracellular oxidative stress.

Animals↗
PubMed2004

Platelet-derived growth factor induces tissue factor expression in vascular smooth muscle cells via activation of Egr-1.

Activation of vascular smooth muscle cells (SMCs) by platelet-derived growth factor (PDGF) is a seminal event in the initiation and progression of the atherosclerotic lesion and may contribute to atherosclerotic plaque instability with plaque rupture and thrombus formation. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play a major role in thrombus formation after plaque rupture. This study examined intracellular signaling pathways leading to TF expression and Egr-1 activation, a key element in tissue factor transcription, by PDGF-BB in rat SMCs. PDGF-BB induced TF mRNA and protein expression in a time-dependent manner. Early growth response factor-1 (Egr-1) binding activity was also induced by PDGF-BB, as well as phosphorylation of extracellular signal-regulated kinase. PDGF-BB-induced Egr-1 activation was suppressed by inhibitors of 2 upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and Src family kinases, whereas antioxidants, phosphatidylinositol 3-phosphate kinase, and p38 MAPK inhibitors had no effect. PDGF-BB-stimulated expression of the transcriptional co-repressor NAB2 was time-dependent. Furthermore, transient transfections of SMCs with wild-type and mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of PDGF-BB-induced TF expression. Taken together, the results suggest that PDGF-BB induces TF expression and activity in SMC by a Src family kinases/ERK/Egr-1 signaling pathway and may therefore contribute to thrombus formation in advanced atherosclerosis and restenosis.

Animals↗
PubMed2005

Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A(2B) receptors.

The objectives of the present study were to determine whether adenosine attenuates proliferation of glomerular mesangial cells (GMCs), which adenosine receptor (AR) mediates the antimitogeneic actions of adenosine, and the cellular mechanisms by which adenosine inhibits growth of GMCs. Studies were conducted in both human and rat GMCs. Platelet-derived growth factor (PDGF)-BB (25 ng/mL) increased DNA synthesis ([3H]thymidine incorporation), cellular proliferation (cell number), collagen synthesis ([3H]proline incorporation), and mitogen-activated protein kinase (MAPK) activity, and these effects were attenuated by 2-chloroadenosine (nonselective AR agonist) and 5'-N-methylcarboxamidoadenosine (MECA; nonselective AR agonist), but not by N6-cyclopentyladenosine (selective A1 AR agonist), AB-N-MECA (selective A3 AR agonist), or CGS21680 (selective A(2A) AR agonist). KF17837 (selective A(2A/B) AR antagonist) and 1,3-dipropyl-8-p-sulfophenylxanthine (nonselective AR antagonist), but not 8-cyclopentyl-1,3-dipropylxanthine (selective A1 AR antagonist), blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-MECA. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor increased both basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis, and the growth-inhibitory effects of 2-chloroadenosine, 5'-N-MECA, and erythro-9-(2-hydroxy-3-nonyl)adenine (inhibitor of adenosine deaminase) plus iodotubercidin (inhibitor of adenosine kinase) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. We conclude that adenosine causes inhibition of GMC growth by activating A(2B) receptors coupled to inhibition of MAPK activity. A(2B) receptors may play an important role in regulating glomerular remodeling associated with GMC proliferation. Pharmacological or molecular biologic activation of A(2B) receptors may prevent glomerular remodeling associated with glomerulosclerosis, renal disease, and abnormal growth associated with hypertension and diabetes.

Adenosine↗