FGFR1 mediates recombinant thrombomodulin domain-induced angiogenesis
| Autor: | Cheng Hsiang Kuo, Tai Tzu Hsieh, Guey Yueh Shi, Yu Ching Huang, Hua Lin Wu, Meng Chen Sung, Po Ku Chen, Chia Fong Cho, Fang Tzu Lee, Yi-Heng Li, Chwan Yau Luo, Bi Ing Chang |
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| Rok vydání: | 2014 |
| Předmět: |
Physiology
Angiogenesis Thrombomodulin Neovascularization Physiologic Biology Umbilical vein Rats Sprague-Dawley Neovascularization Mice Ischemia Physiology (medical) Human Umbilical Vein Endothelial Cells medicine Animals Humans Corneal Neovascularization Receptor Fibroblast Growth Factor Type 1 Phosphorylation Protein Kinase Inhibitors Tube formation Mice Inbred BALB C Fibroblast growth factor receptor 1 Molecular biology Recombinant Proteins Hindlimb Protein Structure Tertiary Rats stomatognathic diseases HEK293 Cells Pyrimidines Fibroblast growth factor receptor Gene Knockdown Techniques Angiogenesis Inducing Agents Syndecan-4 medicine.symptom Cardiology and Cardiovascular Medicine Protein C |
| Zdroj: | Cardiovascular Research. 105:107-117 |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | Aims The recombinant epidermal growth factor-like domain plus the serine/threonine-rich domain of thrombomodulin (rTMD23) promotes angiogenesis and accelerates the generation of activated protein C (APC), which facilitates angiogenesis. The aim of this study was to elucidate the molecular mechanisms underlying the angiogenic activity of rTMD23. Methods and results We prepared rTMD23 and its mutants that did not possess the ability to promote APC generation and investigated their angiogenic activities in vitro and in vivo . rTMD23 mutants promoted proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro and induced neovascularization in vivo ; these effects were similar to those exerted by wild-type rTMD23. To investigate its interaction with rTMD23, Type I fibroblast growth factor receptor (FGFR1) was precipitated along with syndecan-4 by rTMD23-conjugated Sepharose in human umbilical vein endothelial cells and FGFR1-expressing human embryonic kidney 293 cells. Additionally, the kinetics of the interaction between rTMD23 and FGFR1 were analysed using surface plasmon resonance. rTMD23-induced FGFR1 activation and tube formation were inhibited by an FGFR1-specific tyrosine kinase inhibitor, PD173074, or by knockdown of FGFR1 using siRNA technology. We observed an improvement in rat hindlimb recovery in an ischaemic model following rTMD23 treatment, and this was associated with increased neovascularization and FGFR1 phosphorylation. Conclusion rTMD23 induced angiogenesis via FGFR1, a process that is independent of the APC pathway. |
| Databáze: | OpenAIRE |
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