Inhibition of PHD3 by salidroside promotes neovascularization through cell–cell communications mediated by muscle-secreted angiogenic factors

• Published in: Scientific reports 2017-03, Vol.7 (1), p.43935-43935, Article 43935
• Main Authors: Zhang, Jing, Kasim, Vivi, Xie, Yu-Dan, Huang, Can, Sisjayawan, Julita, Dwi Ariyanti, Agnes, Yan, Xue-Song, Wu, Xiao-Yan, Liu, Cai-Ping, Yang, Li, Miyagishi, Makoto, Wu, Shou-Rong
• Format: Article
• Language: English
• Subjects: 13; 13/89; 13/95; 14; 14/19; 38; 59; 64; 64/60; 692/308/153; 692/699/75/593/1920; 96; 96/2; Angiogenesis; Angiogenesis Inducing Agents - metabolism; Animals; Cell adhesion & migration; Cell Communication; Cell Line; Cell migration; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - physiology; Estrogens; Fibroblast growth factor 2; Glucosides - administration & dosage; Hindlimb; Humanities and Social Sciences; Humans; Hydroxylase; Injections, Intramuscular; Ischemia; Ischemia - drug therapy; Mice, Inbred BALB C; multidisciplinary; Muscle Cells - drug effects; Muscle Cells - physiology; Musculoskeletal system; Neovascularization, Physiologic - drug effects; Paracrine signalling; Perfusion; Phenols - administration & dosage; Platelet-derived growth factor; Platelet-derived growth factor BB; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Rodents; Science; Skeletal muscle; Smooth muscle; Transcription; Vascular diseases; Vascularization
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep43935

Therapeutic angiogenesis has been considered as a potential strategy for treating peripheral artery diseases including hind-limb ischemia (HLI); however, no effective drug-based treatment is currently available. Here we showed that intramuscular administration of salidroside, an active compound of Chinese herb Rhodiola , could robustly enhance blood perfusion recovery by promoting neovascularization in HLI mice. We revealed that salidroside promoted skeletal muscle cell migration and paracrine function through inhibiting the transcriptional level of prolyl-hydroxylase domain 3 (PHD3) without affecting PHD1 and PHD2. Paracrine signals from salidroside-treated skeletal muscle cells enhanced endothelial and smooth muscle cells migration, while inhibition of FGF2/FGF2R and PDGF-BB/PDGFR-β pathways abolished this effect, as well as neovascularization in HLI mice. Furthermore, we elucidated that salidroside inhibition on PHD3 might occur through estrogen receptor alpha (ERα). Together, our findings highlights the potential application of salidroside as a novel pharmalogical inhibitor of ERα/PHD3 axis for therapeutic angiogenesis in HLI diseases.