Natural compound bavachalcone promotes the differentiation of endothelial progenitor cells and neovascularization through the RORα-erythropoietin-AMPK axis
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Shuang Ling1,*, Rong-Zhen Ni1,2,*, Yunyun Yuan1, Yan-Qi Dang1, Qian-Mei Zhou1, Shuang Liang2, Fujiang Guo3, Wei Feng4, Yuanyuan Chen1, Katsumi Ikeda5, Yukio Yamori6 and Jin-Wen Xu1
1Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
2Engineering Research Center of Modern Preparation Technology of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
3School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
4School of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
5School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan
6Institute for World Health Development, Mukogawa Women's University, Nishinomiya, Japan
*These authors have contributed equally to the work
Jin-Wen Xu, email: [email protected]
Keywords: endothelial progenitor cell, bavachlcone, neovascularization, RORα, erythropoietin
Received: June 14, 2017 Accepted: August 06, 2017 Published: September 16, 2017
In cardiovascular diseases, endothelial function is impaired and the level of circulating endothelial progenitor cells (EPCs) is low. This study investigated whether the natural bioactive component bavachalcone (BavaC) induces the differentiation of EPCs and neovascularization in vivo; the underlying mechanisms were also examined. We observed that the treatment of rat bone marrow–derived cells with a very low dose of BavaC significantly promoted EPC differentiation. In our hindlimb ischemia models, low–dose BavaC administered orally for 14 days stimulated the recovery of ischemic hindlimb blood flow, increased circulating EPCs, and promoted capillary angiogenesis. The BavaC treatment of rat bone marrow cells for 24 h initiated the AMP–activated protein kinase (AMPK) activity required for the differentiation of EPCs. Further testing revealed that BavaC and CGP52608, a retinoic acid receptor–related orphan receptor α (RORα) activator, enhanced the activity of RORα1 and EPO luciferase reporter gene. BavaC treatment also elevated EPO mRNA and protein expression in vitro and in vivo and the circulating EPO levels in rats. By contrast, the RORα antagonist VPR66 inhibited BavaC–induced EPO reporter activity, and differentiation of bone marrow cells into endothelial progenitor cells. Overall, this study revealed that BavaC promotes EPC differentiation and neovascularization through a RORα–EPO–AMPK axis. BavaC can be used as a promising angiogenesis agent for enhancing angiogenesis and tissue repair.
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