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

研究成果: 雜誌貢獻文章

59 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)1627-1636
頁數10
期刊Circulation
111
發行號13
DOIs
出版狀態已發佈 - 四月 5 2005
對外發佈Yes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Shi, C. S., Shi, G. Y., Chang, Y. S., Han, H. S., Kuo, C. H., Liu, C., Huang, H. C., Chang, Y. J., Chen, P. S., & 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