Thrombin promotes angiogenesis by a mechanism independent of fibrin formation

Tsopanoglou, Nikos E.; Pipili-Synetos, Eva; Maragoudakis, Michael E.

doi:10.1152/ajpcell.1993.264.5.c1302

Cited by 117 publications

(87 citation statements)

References 27 publications

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“…In fact, PARs have been suggested to play little role in the inflammatory responses in experimental endotoxemia. 74 Furthermore, the thrombininduced increase in vascular permeability and angiogenesis [75][76][77][78] may also contribute to pathophysiology in vascular lesions (Figure).…”

Section: Par2mentioning

confidence: 99%

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Hirano

2007

ATVB

136

121

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Abstract-Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. (Arterioscler Thromb Vasc Biol. 2007;27:27-36.)

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Section: Par2mentioning

confidence: 99%

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Hirano

2007

ATVB

136

121

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“…Thrombin induces angiogenesis in vivo via cleavage of the tethered ligand of the thrombin receptor on endothelial cells without the requirement for fibrin formation (40). Simultaneously, these two aminoterminal kringle domains of prothrombin are released.…”

Section: Negative Regulators Of Angiogenesis Within Coagulation Cascadementioning

confidence: 99%

The Hemostatic System as a Regulator of Angiogenesis

Browder¹,

Folkman²,

Pirie-Shepherd³

2000

Journal of Biological Chemistry

298

215

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Angiogenesis is the process of sprouting and configuring new blood vessels from pre-existing blood vessels, whereas the hemostatic system maintains the liquid flow of blood by regulating platelet adherence and fibrin deposition. Both systems normally appear quiescent, yet both systems remain poised for repair of injury. With vessel injury, a rapid sequence of reactions must occur to occlude the vessel wall defect and prevent hemorrhage. Activated platelets link the margins of the defect and form a provisional barrier that is quickly enmeshed with polymerized fibrin. This clot structure initially requires immobilized vascular endothelial cells to anchor the clot and prevent further bleeding. Thereafter, endothelial cells at the clot margins become mobile, dismantling and invading the cross-linked fibrin structure to rebuild a new vessel wall.Although the positive and negative regulators that control the delicate balance of platelet reactivity and fibrin deposition have been elucidated over the past four decades, analogous proteins that control endothelial cell growth and inhibition have only been discovered within the past decade. Hemostasis and angiogenesis are becoming increasingly inter-related. Proteins generated by the hemostatic system coordinate the spatial localization and temporal sequence of clot/endothelial cell stabilization followed by endothelial cell growth and repair of a damaged blood vessel. We focus here on the regulation of angiogenesis during vessel repair mediated by proteins secreted by platelets and derived as cryptic fragments from the coagulation cascade and fibrinolytic system.

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“…The various cleavage products of fibrinogen and fibrin induce capillary tube formation. Both thrombin and fibrin have been shown to promote angiogenesis (8,55).…”

Section: Tgf-␤1 Treatment Of Baec Aggregates Cultured In a Fibrin Matmentioning

confidence: 99%

Role of TGF-β1 and JNK signaling in capillary tube patterning

Bein¹,

Odell-Fiddler²,

Drinane³

2004

American Journal of Physiology-Cell Physiology

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factor (TGF) family of secretory polypeptides comprises signaling proteins involved in numerous physiological processes, including vascular development and vessel wall integrity. Both pro-and antiangiogenic effects of TGF-␤1 have also been documented. To study the intracellular mechanisms involved in capillary tube morphogenesis, endothelial cell aggregates were cultured in a fibrin matrix. It was found that the pattern of capillary tubes formed in a fibrin matrix was altered in response to TGF-␤1 treatment such that the capillary-like structures displayed a bipolarized pattern. In contrast, in untreated control and fibroblast growth factor-2-treated cells, the pattern of capillary tubes formed was random. TGF-␤1 also downregulated urokinase-type plasminogen activator (uPA) activity while upregulating PA inhibitor (PAI)-1 and thrombospondin (TSP)1 gene expression. To investigate the signaling cascade mediating the phenotypic changes observed, pharmacological inhibitors of p38 MAPK, Sp1 transcription factor, c-Jun NH2-terminal kinase (JNK), and the cytokine TNF-␣ were used. The p38 MAPK inhibitor SB203580 reversed the TGF-␤1-dependent inhibition of uPA activity but not its morphogenetic effect. In contrast, the DNA intercalator WP631 and TNF-␣ counteracted the TGF-␤1-induced morphogenetic effect while the JNK inhibitor SP600125 effectively inhibited capillary tube formation. These results indicate that the TGF-␤1-induced capillary tube pattern is independent of the p38 MAPK-activated PAI-1 and TSP1 expression, but the mechanism involves Sp1-dependent transcriptional regulation. The results also raise the possibility that the JNK pathway, which controls convergent extension in Xenopus, may be involved in vessel wall patterning in mammalian systems. metalloproteinase; plasminogen activator; p38 MAPK; thrombospondin 1; Sp1 THE DEVELOPMENTAL PROCESSES of blood vessel formation and organogenesis are intimately coordinated. Endothelial cells that arise from angioblast clumps, in conjunction with associated cells and the extracellular matrix, organize into a complex network of blood vessels and form a hierarchical tubular system commonly known as the vascular tree. As exemplified by the vasculature in the lungs and the heart, the vascular system develops a pattern that matches the anatomical architecture and physiological requirements of different parts of the body. The microenvironment in different vascular beds provides guidance signals that direct a given vascular pattern. Although many secreted and cell-associated molecules critical for vasculogenesis and angiogenesis are known, the cellular and molecular mechanisms underlying vascular patterning and, in particular, the cues for cellular assembly into vessels are not well understood.The matrix proteins in the microenvironment are known to modulate cellular activities. On the basis of studies performed using fibronectin, collagen, matrigel, and fibrin matrices, it has been proposed that traction forces exerted by cells on viscoelastic substrata induce reorganization ...

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Thrombin promotes angiogenesis by a mechanism independent of fibrin formation

Cited by 117 publications

References 27 publications

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

The Hemostatic System as a Regulator of Angiogenesis

Role of TGF-β1 and JNK signaling in capillary tube patterning

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