Celastrol inhibits vasculogenesis by suppressing the VEGF-induced functional activity of bone marrow-derived endothelial progenitor cells.
Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in tumor vasculogenesis because they provide both instructive (release of pro-angiogenic cytokines, such as VEGF) and structural (vessel incorporation and stabilization) functions. Celastrol, derived from Trypterygium wilfordii Hook F., a traditional Chinese medicine plant, has been studied for its antitumorigenic properties, but its mechanism of action is not well understood. The aims of this study are to investigate the effects of Celastrol on VEGF-induced functional activity of BM-EPCs and to identify any mechanisms associated with this process. Here, we show that Celastrol attenuates VEGF secretion in BM-EPCs in vitro. This attenuation, in turn, inhibits the in vitro VEGF-induced cell viability, cell-cell adhesion, cell-ECM adhesion, migration response and vascular tube formation of BM-EPCs. Additionally, Celastrol inhibits the phosphorylation of VEGFR2, endothelial nitric oxide synthase (eNOS), and Akt to attenuate cell functions. Taken together, the present study demonstrates that Celastrol decreases Akt/eNOS signaling in BM-EPCs in vitro. These findings identify novel mechanisms that regulate EPC function and may provide new insights for the medicinal use of Celastrol.
Department of Orthopaedic Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655 Guangzhou, China.
Shuai
S
Huang
Yubo
Y
Tang
Xingdong
X
Cai
Xinsheng
X
Peng
Xingmo
X
Liu
Longjuan
L
Zhang
Yucheng
Y
Xiang
Dechun
D
Wang
Xi
X
Wang
Tao
T
Pan
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001854:Bone Marrow Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D055806:Microvessels / Q000187:drug effects / Q000648:ultrastructure; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; C050414:celastrol