Thrombin and Vascular Smooth Muscle Cell Proliferation: Implications for Atherosclerosis and Restenosis

McNamara, Coleen A.; Sarembock, Ian J.; Bachhuber, Brian G.; Stouffer, George A.; Ragosta, Michael; Barry, William L.; Gimple, Lawrence W.; Powers, Eric R.; Owens, Gary K.

doi:10.1055/s-2007-999001

Cited by 76 publications

(54 citation statements)

References 43 publications

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“…[15][16][17] Second, thrombin is a potent mitogen for cultured SMCs. 18,19 Accordingly, the thrombin-specific inhibitor hirudin significantly reduces intima formation in various animal models. 20 -22 Third, the presence of active thrombin, as well as active PAI-1, was reported in human atherosclerotic lesions.…”

Section: See Page 1943mentioning

confidence: 99%

Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model

Waard

Arkenbout

Carmeliet

et al. 2002

ATVB

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Objective-We previously reported that plasminogen activator inhibitor 1 (PAI-1), in the presence of vitronectin (VN), inhibits thrombin activity in vitro. Furthermore, we demonstrated in human atherosclerotic plaques the colocalization of thrombin, PAI-1, and VN, as well as activity of thrombin and PAI-1. Here, we show that PAI-1 is a local thrombin inhibitor in vivo. Methods and Results-We used the murine carotid artery ligation model to assess the role of PAI-1 and VN in stenosis by using PAI-1-deficient (PAI-1 See page 1943Delineating the role of PAI-1 in atherogenesis and restenosis is particularly cumbersome, partially as a result of the different design of experimental models that often accentuate a single feature of the human pathology. For instance, comparison of mechanical and electrical injury-induced intima formation in PAI-1-deficient ( Ϫ/Ϫ ) and wild-type mice revealed that PAI-1 blocks intimal thickening by inhibiting the migration of SMCs. 3 Moreover, PAI-1-overexpressing SMCs, seeded on a denuded carotid artery, inhibited intima formation as the result of decreased SMC migration. 4 In contrast, by using a copper-or ferrichloride-induced oxidative vascular injury model, PAI-1 deficiency attenuated lesion formation. 5-7 Contradictory observations have been noted in high-fat, macrophage-rich/ SMC-poor models (apoE Ϫ/Ϫ and/or LDLR Ϫ/Ϫ mice), revealing that PAI-1 deficiency may reduce, enhance, or not influence lesion formation, possibly depending on strain differences. 8 -10 In addition, in a balloon-injured rat carotid artery model, PAI-1 overexpression resulted in increased SMC proliferation that was associated with fibrin accumulation. 11 In the murine carotid artery ligation model, formation of a fibrin matrix apparently accounted for increased intima formation in uPA Ϫ/Ϫ mice, whereas PAI-1 Ϫ/Ϫ mice responded like wild-type mice. 12 However, in similar study that used the carotid artery ligation model, decreased intima formation was observed in VN Ϫ/Ϫ and PAI-1 Ϫ/Ϫ mice. 7 A satisfactory explanation for these discrepancies is presently not available, but it is possible that the different models and/or methodologies accentuate the various, distinct functions of PAI-1.Here, we studied the role of PAI-1 as a local thrombin inhibitor in SMC proliferation by using the carotid artery ligation model, which mimics restenosis after angioplasty. In this model, the endothelium remains intact, and lesions virtually lack infiltrating cells. 13 It is assumed that reduced shear stress, hypoxia, and arterial wall pressure are determinants for intima formation as a result of SMC proliferation. 14 A possible function for PAI-1 in controlling SMC proliferation is suggested by the following observations and explored in this study. First, PAI-1 inhibits thrombin in vitro, provided either VN or heparin is present as a cofactor. [15][16][17] Second, thrombin is a potent mitogen for cultured SMCs. 18,19 Accordingly, the thrombin-specific inhibitor hirudin significantly reduces intima formation in various animal model...

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Section: See Page 1943mentioning

confidence: 99%

Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model

Waard

Arkenbout

Carmeliet

et al. 2002

ATVB

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“…In cardiovascular diseases, such as hypertension, atherosclerosis, and restenosis after angioplasty, vascular remodeling clearly requires rearrangement of VSMC cytoskeleton and focal adhesions (9,43). Both thrombin and angII are thought to have important roles in remodeling by virtue of their effects on VSMC migration and growth (1,3,44). The receptors for both thrombin and angII are highly expressed in atherosclerotic plaque and in restenotic lesions after balloon arterial injury (5-7).…”

Section: Figurementioning

confidence: 99%

“…Thrombin is a key regulator of the coagulation cascade and plays pivotal roles in thrombosis formation at atherosclerotic lesions or after balloon angioplasty. Both angII and thrombin activate signaling pathways that induce cell proliferation, hypertrophy, and migration of vascular smooth muscle cells (VSMCs) (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require c-Src

et al. 1999

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Thrombin and angiotensin II (angII) have trophic properties as mediators of vascular remodeling. Focal adhesions and actin cytoskeleton are involved in cell growth, shape, and movement and may be important in vascular remodeling. To characterize mechanisms by which thrombin and angII modulate vessel structure, we studied the effects of these G protein-coupled receptor ligands on focal adhesions in vascular smooth muscle cells (VSMCs). Both thrombin and angII stimulated bundling of actin filaments to form stress fibers, assembly of focal adhesions, and protein tyrosine phosphorylation at focal adhesions, such as p130Cas, paxillin, and tensin. To test whether c-Src plays a critical role in focal adhesion rearrangement, we analyzed cells with altered c-Src activity by retroviral transduction of wild-type (WT) and kinase-inactive (KI) c-Src into rat VSMCs, and by use of VSMCs from WT (src +/+ ) and Src-deficient (src -/-) mice. Tyrosine phosphorylation of Cas, paxillin, and tensin were markedly decreased in VSMCs expressing KI-Src and in src -/-VSMCs. Expression of KI-Src did not inhibit stress fiber formation by thrombin. Surprisingly, actin bundling was markedly decreased in VSMCs from src -/-mice both basally and after thrombin stimulation, compared with src +/+ mice. We also studied the effect of KI-Src and WT-Src on VSMC spreading. Expression of KI-Src reduced the rate of VSMC spreading on collagen, whereas WT-Src enhanced cell spreading. In conclusion, c-Src plays a critical role in agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in VSMCs. c-Src kinase activity is required for the cytoskeletal turnover that occurs in cell spreading, whereas c-Src appears to regulate actin bundling via a kinase-independent mechanism.

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“…In addition, stimulation of the thrombin receptor signals many cellular events that are associated with the response to vascular injury, including smooth muscle cell proliferation. 1 Thrombin activates platelets and regulates the actions of other cells by means of G protein-coupled protease-activated receptors (PARs). PAR1 is activated when thrombin binds to and cleaves the amino terminal extension of its receptor to create a new receptor amino terminus that functions as a tethered ligand ( Figure).…”

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confidence: 99%

Thrombin, Thrombomodulin, and Extracellular Signal–Regulated Kinases Regulating Cellular Proliferation

Freedman¹

2001

Circulation Research

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T hrombin, a coagulation protease, is primarily known for its regulation of hemostasis and thrombosis. However, this enzyme also plays important roles in wound healing and pathological situations, such as inflammation and tumorigenesis. In addition, stimulation of the thrombin receptor signals many cellular events that are associated with the response to vascular injury, including smooth muscle cell proliferation. 1 Thrombin activates platelets and regulates the actions of other cells by means of G protein-coupled protease-activated receptors (PARs). PAR1 is activated when thrombin binds to and cleaves the amino terminal extension of its receptor to create a new receptor amino terminus that functions as a tethered ligand (Figure). 2 This new amino terminus then binds intramolecularly to the body of the receptor to effect transmembrane signaling. 3 In response to stimulation with thrombin, endothelial cells release prostaglandin I 2 and von Willebrand factor and undergo cellular proliferation.Thrombomodulin (TM), a membrane-bound glycoprotein expressed on endothelial cells, has a high affinity of binding to thrombin and converts thrombin from a procoagulant to an anticoagulant. TM binds to thrombin and changes the enzyme's conformation, allowing thrombin to activate protein C (Figure). Plasma-soluble TMs are cleaved products of cellular TM that also have anticoagulant and antifibrinolytic properties, and plasma levels may reflect the level of endothelial TM expression. 4 Prospective studies show that high plasma TM levels are associated with a low risk of developing coronary heart disease. 4 It has also been shown that overexpression of TM on smooth muscle cells downregulates proliferation, 5 suggesting that TM could regulate endothelial and smooth muscle cell proliferation via PAR1.Cellular proliferation is also regulated by specific mitogenactivated protein kinases (MAPKs) that translocate into nuclei after activation and play critical roles in connecting the signal to gene expression and allowing cell-cycle entry. MAPKs (p42/p44 MAPK, also called extracellular signalregulated kinase [ERK] 1 and ERK2) are key mediators of signal transduction from the cell surface to the nucleus. Activation of p42/p44 MAPK required for transduction of mitogenic signaling is associated with a rapid nuclear translocation of these kinases. 6 Addition of the pharmacological MAPK inhibitor PD 98059 has been shown to block activation of the p42/p44 MAPK pathway, impeding its nuclear accumulation. It is believed that MAPK nuclear translocation requires both activation of the p42/p44 MAPK module and neosynthesis of short-lived proteins thought to be nuclear anchors. 7 MAPK modules, composed of three protein kinases activated by successive phosphorylation, are involved in the signal transduction of a wide range of extracellular agents. MAPK is only active when both tyrosyl and threonyl residues are phosphorylated, suggesting that the enzyme functions in vivo to integrate signals from two distinct transduction pathways. 8 In mammalian cel...

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Thrombin and Vascular Smooth Muscle Cell Proliferation: Implications for Atherosclerosis and Restenosis

Cited by 76 publications

References 43 publications

Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model

Plasminogen Activator Inhibitor 1 and Vitronectin Protect Against Stenosis in a Murine Carotid Artery Ligation Model

Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require c-Src

Thrombin, Thrombomodulin, and Extracellular Signal–Regulated Kinases Regulating Cellular Proliferation

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