Enhancement of incisional wound healing and neovascularization in normal rats by thrombin and synthetic thrombin receptor-activating peptides.

Carney, Darrell H.; Mann, Richard H.; Redin, W R; Pernia, S D; Berry, Donna M.; Heggers, John P.; Hayward, Peter G.; Robson, Martin C.; Christie, John D.; Annable, C. R.

doi:10.1172/jci115737

Cited by 149 publications

(84 citation statements)

References 39 publications

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“…These proteins are potent mitogens for vascular SMCs in vitro (Scott-Burden et al 1991, McNamara et al 1993, Weber et al 1994 and also induce extracellular matrix formation (Scott-Burden et al 1990, Carney et al 1992. AII acts by direct activation of the angiotensin type 1 receptor (Sung et al 1994), whereas -thrombin binds to its receptor and, by enzymatic cleavage generates a new amino-terminus 'tethered ligand' which activates the receptor (reviewed in Coughlin 1994).…”

Section: Introductionmentioning

confidence: 99%

Novel cardiovascular actions of the activins

Molloy¹,

Taylor²,

Pawlowski³

1999

Journal of Endocrinology

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Proliferation and directed migration of vascular cells are key components in vascular diseases such as atherosclerosis and restenosis following percutaneous transluminal coronary angioplasty. However, the precise cellular and molecular mechanisms involved in the control of vascular cell proliferation or migration at the tissue level remain largely undefined. Molecules contributing to these processes are elaborated by distinct cell types and act in both autocrine and paracrine modes. They include two broad classes, polypeptide growth factors and vasoactive G-protein-coupled receptor (GPCR) agonists. Examples of the former, such as platelet-derived growth factor, bind to and activate cell surface receptor tyrosine kinases, initiating intracellular biochemical signaling pathways associated with cell proliferation or migration. In contrast, recent evidence suggests that vasoactive GPCR agonists (e.g. angiotensin II, endothelin-1, -thrombin) elicit cell growth indirectly by inducing the production of autocrine or paracrine factors in vascular cells. Recent studies have identified activin A as a novel component of conditioned medium obtained from GPCR agonist-stimulated vascular smooth muscle cells (SMCs). Although activin A alone only weakly stimulated rat aortic SMC DNA synthesis, it demonstrated a potent co-mitogenic effect in combination with either epidermal growth factor (EGF) or heparin binding EGF-like growth factor in these cells, increasing DNA synthesis by up to 5-and 4-fold respectively. Furthermore, in a rat carotid-injury model, activin A mRNA was upregulated within 6 h after injury, followed by increases in immunoreactive protein detected in the expanding neointima 7 to 14 days later. Taken together, these results indicate that activin A is a common vascular SMC-derived growth factor induced by vasoactive agonists that may, either alone or in combination with other factors, contribute to fibroproliferative vascular diseases.

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Section: Introductionmentioning

confidence: 99%

Novel cardiovascular actions of the activins

Molloy¹,

Taylor²,

Pawlowski³

1999

Journal of Endocrinology

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“…1 Although the key molecules involved in these processes are not known, several vasoactive agonists including angiotensin II (AII) and ␣ -thrombin have been implicated. These G-protein-coupled receptor (GPCR) agonists are potent mitogens for rat aortic smooth muscle (RASM) cells in vitro (1)(2)(3)(4)(5)(6) and also induce extracellular matrix formation (7)(8)(9)(10). AII acts by direct activation of the AII type 1 (AT 1 ) receptor (11), whereas ␣ -thrombin binds to its receptor and by enzymatic cleavage, generates a new amino terminus tethered ligand that activates the receptor (for review see ref- erence 12).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

Pawlowski

Taylor²,

Valentine³

et al. 1997

J. Clin. Invest.

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“…8 -10 For example, when thrombin or a PAR-1-activating peptide is applied to incisional skin wounds in rats, wound healing is accelerated. 11 Because both osteoblast proliferation and bone resorption are important components of the process of bone repair, we hypothesized that thrombin, through PAR-1, may participate in this process. The current study was undertaken to investigate this hypothesis, using mice with a targeted disruption of the PAR-1 gene.…”

mentioning

confidence: 99%

The Role of Protease-Activated Receptor-1 in Bone Healing

Song

Pagel

Campbell

et al. 2005

The American Journal of Pathology

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Protease-activated receptor (PAR)-1, a G-protein-coupled receptor activated by thrombin, mediates thrombin-induced proliferation of osteoblasts. The current study was undertaken to define the role of PAR-1 in bone repair. Holes were drilled transversely through the diaphysis of both tibiae of PAR-1-null and wildtype mice. Three days later, fewer cells had invaded the drill site from adjacent bone marrow in PAR-1-null mice than in wild-type mice, and a lower percentage of cells were labeled with [ 3 H]thymidine in PAR-1-null drill sites. More osteoclasts were also observed in the drill site of PAR-1-null mice than in wild-type mice 7 days after drilling. New mineralized bone area was less in the drill site and on the adjacent periosteal surface in PAR-1-null mice than in wildtype mice at day 9. From day 14, no obvious differences could be seen between PAR-1-null and wild-type tibiae. In vitro thrombin caused a dose-dependent increase in proliferation of bone marrow stromal cells isolated from wild-type mice but not PAR-1-null mice. Thrombin stimulated survival of bone marrow stromal cells from both wild-type and PAR-1-null mice, but it did not affect bone marrow stromal cell migration in either wild-type or PAR-1-null cells Thrombin is a serine protease, which plays a central role in blood coagulation through its cleavage of fibrinogen, but also exerts specific receptor-mediated effects on cell function. Three thrombin receptors have been identified, protease-activated receptors (PARs)-1, -3, and -4, which are members of the seven transmembrane domain Gprotein-coupled receptor family. 1,2 Protease-activated receptor-1 is expressed by osteoblasts (bone-forming cells), and mediates thrombin-induced proliferation of these cells. [3][4][5] Thrombin also stimulates osteoclastic bone resorption in vitro. 6,7 Thrombin is generated during tissue injury, and PAR-1 activation appears to be involved in pathological processes including inflammation and wound healing. 8 -10 For example, when thrombin or a PAR-1-activating peptide is applied to incisional skin wounds in rats, wound healing is accelerated. 11 Because both osteoblast proliferation and bone resorption are important components of the process of bone repair, we hypothesized that thrombin, through PAR-1, may participate in this process. The current study was undertaken to investigate this hypothesis, using mice with a targeted disruption of the PAR-1 gene. 12 Fifty percent of these mice die at about day 9.5 of gestation, and the remainder survive to become apparently normal adults. Embryonic death of PAR-1-null mice can be prevented by targeted expression of PAR-1 in endothelial cells. 13 Although PAR-1 is expressed by platelets and mediates platelet aggregation in humans, PAR-1 is not expressed by mouse platelets, and therefore is not required for normal blood coagulation in this species. 14 A number of models of bone repair have been established for use in mice, including an unstabilized fracture model, stabilized fracture models involving internal or external fi...

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Enhancement of incisional wound healing and neovascularization in normal rats by thrombin and synthetic thrombin receptor-activating peptides.

Abstract: To better define thrombin-receptor interactions, we synthesized human thrombin peptides and identified binding-

Cited by 149 publications

References 39 publications

Novel cardiovascular actions of the activins

Novel cardiovascular actions of the activins

Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

The Role of Protease-Activated Receptor-1 in Bone Healing

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