Evidence of human thrombomodulin domain as a novel angiogenic factor

Chung Sheng Shi, Guey Yueh Shi, Yi Sheng Chang, Huai Song Han, Cheng Hsiang Kuo, Che Liu, Huey Chun Huang, Yu Jia Chang, Pin Shern Chen, Hua Lin Wu

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Background - Thrombomodulin is an anticoagulant, endothelial-cell-membrane glycoprotein. A recombinant thrombomodulin domain containing 6 epidermal growth factor-like structures exhibits mitogenic activity. This study explored the novel angiogenic effects of the recombinant domain using in vitro and in vivo models. Methods and Results - Human recombinant thrombomodulin containing 6 epidermal growth factor-like structures (TMD2) and TMD2 plus a serine and threonine-rich domain (TMD23) were prepared using the Pichia pastoris expression system. Combined with purified TMD2 or TMD23, thrombin effectively activated protein C. TMD23 had higher activity than TMD2 in stimulating DNA synthesis in cultured human umbilical vein endothelial cells. Additionally, TMD23 stimulated chemotactic motility and capillarylike tube formation in human umbilical vein endothelial cells, an effect mediated through phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase and the phosphatidylinositol-3 kinase/Akt/endothelial nitric oxide synthase pathway. TMD23 also stimulated endothelial cell expression of matrix metalloproteinases and plasminogen activators, which mediated extracellular proteolysis, leading to endothelial cell invasion and migration during angiogenesis. Furthermore, TMD23-containing implants in rat cornea induced ingrowth of new blood vessels from the limbus. With the murine angiogenesis assay, TMD23 not only induced neovascularization coinjected with Matrigel and heparin but also enhanced angiogenesis in Matrigel containing melanoma A2058 cells in nude mice. Conclusions - The recombinant thrombomodulin domain TMD23 enhanced the angiogenic response in vitro and in vivo, suggesting that thrombomodulin fragments may play a role in the formation of new vessels. These findings may provide a new therapeutic option for treating ischemic diseases.

Original languageEnglish
Pages (from-to)1627-1636
Number of pages10
JournalCirculation
Volume111
Issue number13
DOIs
Publication statusPublished - Apr 5 2005
Externally publishedYes

Fingerprint

Thrombomodulin
Angiogenesis Inducing Agents
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Epidermal Growth Factor
Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinase 3
Pichia
Nitric Oxide Synthase Type III
Plasminogen Activators
Mitogen-Activated Protein Kinase 1
Membrane Glycoproteins
p38 Mitogen-Activated Protein Kinases
Threonine
Protein C
Matrix Metalloproteinases
Nude Mice
Thrombin
Cornea
Anticoagulants

Keywords

  • Angiogenesis
  • Endothelium
  • Glycoproteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Shi, C. S., Shi, G. Y., Chang, Y. S., Han, H. S., Kuo, C. H., Liu, C., ... Wu, H. L. (2005). Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation, 111(13), 1627-1636. https://doi.org/10.1161/01.CIR.0000160364.05405.B5

Evidence of human thrombomodulin domain as a novel angiogenic factor. / Shi, Chung Sheng; Shi, Guey Yueh; Chang, Yi Sheng; Han, Huai Song; Kuo, Cheng Hsiang; Liu, Che; Huang, Huey Chun; Chang, Yu Jia; Chen, Pin Shern; Wu, Hua Lin.

In: Circulation, Vol. 111, No. 13, 05.04.2005, p. 1627-1636.

Research output: Contribution to journalArticle

Shi, CS, Shi, GY, Chang, YS, Han, HS, Kuo, CH, Liu, C, Huang, HC, Chang, YJ, Chen, PS & Wu, HL 2005, 'Evidence of human thrombomodulin domain as a novel angiogenic factor', Circulation, vol. 111, no. 13, pp. 1627-1636. https://doi.org/10.1161/01.CIR.0000160364.05405.B5
Shi CS, Shi GY, Chang YS, Han HS, Kuo CH, Liu C et al. Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation. 2005 Apr 5;111(13):1627-1636. https://doi.org/10.1161/01.CIR.0000160364.05405.B5
Shi, Chung Sheng ; Shi, Guey Yueh ; Chang, Yi Sheng ; Han, Huai Song ; Kuo, Cheng Hsiang ; Liu, Che ; Huang, Huey Chun ; Chang, Yu Jia ; Chen, Pin Shern ; Wu, Hua Lin. / Evidence of human thrombomodulin domain as a novel angiogenic factor. In: Circulation. 2005 ; Vol. 111, No. 13. pp. 1627-1636.
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