title: Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice.
abstract: Diabetic mellitus (DM) patients are at an increased risk of developing peripheral arterial disease (PAD). Danhong injection (DHI) is a Chinese patent medicine widely used for several cardiovascular indications but the mechanism of action is not well-understood. We investigated the therapeutic potential of DHI on experimental PAD in mice with chemically induced as well as genetic (KKAy) type 2 DM and the overlapping signaling pathways regulating both therapeutic angiogenesis and glucose homeostasis. Compared with normal genetic background wild type (WT) mice, both DM mice showed impaired perfusion recovery in hind-limb ischemia (HLI) model. DHI treatment significantly accelerated perfusion recovery, lowered blood glucose and improved glucose tolerance in both DM models. Bioluminescent imaging demonstrated a continuous ischemia-induced vascular endothelial growth factor receptor 2 (VEGFR-2) gene expressions with a peak time coincident with the maximal DHI stimulation. Flow cytometry analysis showed a DHI-mediated increase in endothelial progenitor cell (EPC) mobilization from bone marrow to circulating peripheral blood. DHI administration upregulated the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor-2 (VEGFR-2) in ischemic muscle. A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of VEGF-A/VEGFR-2 and peroxisome proliferator-activated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes. We confirmed that upregulation of VEGF-A/VEGFR-2 by DHI promoted PPARδ gene expression in both type 2 diabetic mice. Our findings demonstrated that a multi-component Chinese medicine DHI effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of VEGF-A/VEGFR-2 and PPARδ signaling pathways.
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: He
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
authors.forename: Tiechan
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Department of Medicine-Cardiology and Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, United States of America.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Center of Biomedical Research, Tufts University School of Medicine, Boston, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, and Collaborative Innovation Center for Biotherapy, Nankai University, Tianjin, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors.forename: Xuimei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.|Molecular Cardiology Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D008516:Medicine, Chinese Traditional; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000378:metabolism*; D058729:Peripheral Arterial Disease / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D047494:PPAR delta; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2