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.

Shuang He,David A Goukassian,Jihong Han,Tiechan Zhao,Hao Guo,Yan Zhu,Xuimei Gao,Yanzhi Meng,Gangjian Qin,Xiaoying Wang

doi:10.1371/journal.pone.0167305

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.

Highlights

There is a high prevalence of peripheral artery disease (PAD) and the lower extremities are its most common sites
A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor 2 (VEGFR-2) and peroxisome proliferatoractivated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes
Using the two independent mouse models of diabetic peripheral arterial disease (PAD) described above, we demonstrated that Danhong injection (DHI) effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of Vascular endothelial growth factors (VEGFs)-A/VEGFR-2 and PPARδ signaling pathways

Summary

Introduction

There is a high prevalence of peripheral artery disease (PAD) and the lower extremities are its most common sites. Vascular endothelial growth factors (VEGFs), well-known pro-angiogenic factors involved in blood vessel growth during development and post-natal angiogenesis [4], mediate their biological effects through binding to their receptors, VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2). Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that belongs to the nuclear receptor super-family, which includes PPARα and PPARγ Among these three isotypes, PPARδ is the most important regulator for executing key cellular functions in the heart, liver, colon, and skeletal muscle. PPARδ is the most important regulator for executing key cellular functions in the heart, liver, colon, and skeletal muscle Both in vitro and in vivo studies have shown that PPARδ is proangiogenic and plays an important role in the activation of angiogenic pathways [5]

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