WKYMVm-Induced Activation of Formyl Peptide Receptor 2 Stimulates Ischemic Neovasculogenesis by Promoting Homing of Endothelial Colony-Forming Cells

Authors

  • Soon Chul Heo,

    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Yang Woo Kwon,

    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Il Ho Jang,

    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Geun Ok Jeong,

    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Jung Won Yoon,

    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Chi Dae Kim,

    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Sang Mo Kwon,

    1. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
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  • Yoe-Sik Bae,

    1. Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
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  • Jae Ho Kim

    Corresponding author
    1. Medical Research Center for Ischemic Tissue Regeneration, Yangsan, Gyeongsangnam-do, Republic of Korea
    2. Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
    3. Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, Republic of Korea
    • Correspondence: Jae Ho Kim, Ph.D., Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Gyeongsangnam-do, Republic of Korea. Telephone: 82-51-510-8073; Fax: 82-51-510-8076; e-mail: jhkimst@pusan.ac.kr

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Abstract

Endothelial colony-forming cells (ECFCs) are recruited to the sites of ischemic injury in order to contribute to neovascularization and repair of injured tissues. However, therapeutic potential of ECFCs is limited due to low homing and engraftment efficiency of transplanted ECFCs. The G-protein-coupled formyl peptide receptor (FPR) 2 has been implicated in regulation of inflammation and angiogenesis, while the role of FPR2 in homing and engraftment of ECFCs and neovascularization in ischemic tissues has not been fully defined. This study was undertaken to investigate the effects of WKYMVm, a selective FPR2 agonist isolated by screening synthetic peptide libraries, on homing ability of ECFCs and vascular regeneration of ischemic tissues. WKYMVm stimulated chemotactic migration, angiogenesis, and proliferation ability of human ECFCs in vitro. Small interfering RNA-mediated silencing of FPR2, but not FPR3, abrogated WKYMVm-induced migration and angiogenesis of ECFCs. Intramuscular injection of WKYMVm resulted in attenuation of severe hind limb ischemia and promoted neovascularization in ischemic limb. ECFCs transplanted via tail vein into nude mice were incorporated into capillary vessels in the ischemic hind limb, resulting in augmented neovascularization and improved ischemic limb salvage. Intramuscular injection of WKYMVm promoted homing of exogenously administered ECFCs to the ischemic limb and ECFC-mediated vascular regeneration. Silencing of FPR2 expression in ECFCs resulted in abrogation of WKYMVm-induced in vivo homing of exogenously transplanted ECFCs to the ischemic limb, neovascularization, and ischemic limb salvage. These results suggest that WKYMVm promotes repair of ischemic tissues by stimulating homing of ECFCs and neovascularization via a FPR2-dependent mechanism. Stem Cells 2014;32:779–790

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