Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation.

Lai, Kaihua; Wang, Hong; Lee, Wen Sen; Jain, Mukesh K.; Lee, Mu En; Haber, Edgar

doi:10.1172/jci118949

Cited by 102 publications

(71 citation statements)

References 34 publications

(34 reference statements)

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“…All these events may occur in the vessel wall after plaque rupture. Although previous reports have demonstrated the activation of MAP kinases in arteries in animal models of balloon injury and neointimal formation, [25][26][27][28] our study provides evidence that TF can link activation of blood coagulation and SMC proliferation. In this respect, inhibition of these new functions of TF may represent a novel, attractive therapeutic target.…”

Section: Discussioncontrasting

confidence: 61%

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

et al. 2004

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Background-Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation. Methods and Results-Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3 H]thymidine incorporation and direct cell counting, whereas no response was observed with active site-inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1. Conclusions-These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis. Key Words: coagulants Ⅲ signal transduction Ⅲ cell division T issue factor (TF) is a cell surface-anchored glycoprotein that binds both the zymogen factor VII (FVII) and the active serine protease factor VIIa (FVIIa). 1 TF/FVIIa complex activates coagulation by cleaving its natural substrates, factors IX and X, ultimately leading to thrombin generation, fibrin deposition, and platelet activation. 1,2 On these grounds, TF has been considered to function as a major initiator of blood coagulation in vivo. Recently, however, some evidence has suggested that TF may mediate important coagulationindependent biological phenomena, including embryonic and oncogenic angiogenesis, 3,4 and inflammation. 5 In addition, recent data indicate that TF/FVIIa interaction may activate different intracellular signals, culminating in a variety of cell responses, thus suggesting a role for TF as a "true" cell membrane receptor. For example, TF/FVIIa interaction has been shown to be a strong chemotactic stimulus for smooth muscle cells (SMCs), mediating their migration in vitro. 6 FVIIa has been also shown to induce phosphorylation of the extracellular signalregulated kinases 1 and 2 (ERK 1/2) 7 and to upregulate poly(A) polymerase, 8 urokinase-type plasminogen activator receptor, 9 and a host of genes identified with the use of cDNA microarrays. 10 However, despite evidence suggesting close links between TF, activation of coagulation, and intracellular signaling, no direct effects of TF/FVIIa on SMC proliferation have yet been demonstrated. Thus, in the pr...

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Section: Discussioncontrasting

confidence: 61%

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

et al. 2004

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“…5A), indicating that EKR1/2 protein may be related to the antiproliferative activity of docetaxel. ERK1/2 was induced after arterial injury in rats (36), and either an ERK1/2 inhibitor (37) or the gene transfer of an ERK1/2 dominant-negative mutant (38) can suppress VSMC proliferation and block neointimal formation in balloon-injured arteries. Docetaxel produced a marked decrease in the PDGF-BBstimulated phosphorylation of Akt and PLC-γ1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Docetaxel on Platelet-Derived Growth Factor (PDGF)-BB–Induced Proliferation of Vascular Smooth Muscle Cells Through Blocking PDGF-Receptor β Phosphorylation

et al. 2011

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Abstract. The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is an important pathogenic factor for vascular disorders such as atherosclerosis and restenosis after angioplasty. The present study was designed to investigate the inhibitory effects of docetaxel on VSMC proliferation, as well as the molecular mechanism of this inhibition. Docetaxel at 10, 20 and 40 μM significantly inhibited both the proliferation and the DNA synthesis of fetal bovine serum (FBS)-and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs in a concentration-dependent manner. In accordance with these findings, docetaxel blocked the FBS-and PDGF-BB-induced progression of synchronized cells through the G0/G1 phase of the cell cycle. Docetaxel also decreased the expressions of cell cycle-related proteins, including cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, retinoblastoma protein, and proliferative cell nuclear antigen in PDGF-BB-stimulated VSMCs. Docetaxel significantly inhibited the phosphorylation of extracellular signal-regulated kinase 1/2, Akt, and phospholipase C-γ1, downstream molecule in the PDGF-BB signaling pathway. Docetaxel suppressed the phosphorylation of PDGF receptor (PDGF-R) β, the upstream molecule in PDGF-BB signaling cascade, suggesting that the inhibitory effect of docetaxel on the proliferation of VSMCs may occur by blocking PDGF-Rβ phosphorylation. Thus, docetaxel may be a potential antiproliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

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“…However, possible regulation of other signaling molecules by decreased tyrosine phosphatase activities in AT2 receptor null VSMC still remains to be defined. Some tyrosine phosphatases are shown to be critical to embryonic development (40)(41)(42) and regulation of VSMC function (43,44). Tyrosine phosphatases can regulate the development and function of VSMC by dephosphorylating their target substrates, including ERK.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that neointimal VSMC in vascular lesions such as atherosclerosis and restenosis after balloon angioplasty resemble fetal VSMC, rather than adult medial VSMC, in terms of morphology, expression of smooth-muscle specific markers, and growth ability (36,47). Furthermore, ERK is activated in neointimal VSMC (48), and the downregulation of MKP-1 is associated with the activation of ERK after vascular injury (44). Our data may provide an explanation for why these altered growth phenotypes persist in culture.…”

Section: Discussionmentioning

confidence: 99%

Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth

Akishita

Ito²,

Lehtonen³

et al. 1999

J. Clin. Invest.

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Angiotensin II type 2 (AT2) receptor is abundantly expressed in vascular smooth muscle cells (VSMC) of the fetal vasculature during late gestation (embryonic day [15][16][17][18][19][20], during which the blood vessels undergo remodeling. To examine directly the influence of AT2 receptor expression in the developmental biology of VSMC, we studied cultures of VSMC from fetal and postnatal wild-type (Agtr2 + ) and AT2 receptor null (Agtr2 -) mice. Consistent with in vivo data, AT2 receptor binding in cultured Agtr2 + VSMC increased by age, peaking at embryonic day 20, and decreased dramatically after birth. Angiotensin II-induced growth in Agtr2 + VSMC (embryonic day 20) was increased by the AT2 receptor blocker PD123319, indicating that the AT2 receptors are functional and exert an antigrowth effect in Agtr2 + VSMC. Growth of VSMC in response to serum decreased age dependently and was higher in Agtr2 -than in Agtr2 + , inversely correlating with AT2 receptor expression. However, serum-induced growth in Agtr2 + and Agtr2 -VSMC and the exaggerated Agtr2 -VSMC growth was maintained even in the presence of PD123319 or losartan, an AT1 receptor blocker. Moreover, Agtr2 -VSMC showed greater growth responses to platelet-derived growth factor and basic fibroblast growth factor, indicating that Agtr2 -cells exhibit a generalized exaggerated growth phenotype. We studied the mechanism responsible for this phenotype and observed that extracellular signal-regulated kinase (ERK) activity was higher in Agtr2 -VSMC at baseline and also in response to serum. ERK kinase inhibitor PD98059 inhibited both growth and ERK phosphorylation dose-dependently, while the regression lines between growth and ERK phosphorylation were identical in Agtr2 + and Agtr2 -VSMC, suggesting that increased ERK activity in Agtr2 -VSMC is pivotal in the growth enhancement. Furthermore, the difference in ERK phosphorylation between Agtr2 + and Agtr2 -was abolished by vanadate but not by okadaic acid, implicating tyrosine phosphatase in the difference in ERK activity. These results suggest that the AT2 receptor expression during the fetal vasculogenesis influences the growth phenotype of VSMC via the modulation of ERK cascade.

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Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation.

Cited by 102 publications

References 34 publications

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

Inhibitory Effects of Docetaxel on Platelet-Derived Growth Factor (PDGF)-BB–Induced Proliferation of Vascular Smooth Muscle Cells Through Blocking PDGF-Receptor β Phosphorylation

Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth

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