title: Inhibition of PHD3 by salidroside promotes neovascularization through cell-cell communications mediated by muscle-secreted angiogenic factors.
abstract: 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.
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Vivi
authors.initials: V
authors.lastname: Kasim
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Yu-Dan
authors.initials: YD
authors.lastname: Xie
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Can
authors.initials: C
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Julita
authors.initials: J
authors.lastname: Sisjayawan
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Agnes
authors.initials: A
authors.lastname: Dwi Ariyanti
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Xue-Song
authors.initials: XS
authors.lastname: Yan
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Cai-Ping
authors.initials: CP
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.|The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.affiliation: The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.|The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Shou-Rong
authors.initials: SR
authors.lastname: Wu
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005960:Glucosides / Q000008:administration & dosage*; D006614:Hindlimb; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy*; D008807:Mice, Inbred BALB C; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010636:Phenols / Q000008:administration & dosage*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*
chemical_list: D043925:Angiogenesis Inducing Agents; D005960:Glucosides; D010636:Phenols; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C009172:rhodioloside