title: A Novel CXCR4 antagonist enhances angiogenesis via modifying the ischaemic tissue environment.
abstract: Endothelial progenitor cells (EPCs) play a capital role in angiogenesis via directly participating in neo-vessel formation and secreting pro-angiogenic factors. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 play a critical role in the retention and quiescence of EPCs within its niche in the bone marrow. Disturbing the interaction between SDF-1 and CXCR4 is an effective strategy for EPC mobilization. We developed a novel CXCR4 antagonist P2G, a mutant protein of SDF-1β with high antagonistic activity against CXCR4 and high potency in enhancing ischaemic angiogenesis and blood perfusion. However, its direct effects on ischaemic tissue remain largely unknown. In this study, P2G was found to possess a robust capability to promote EPC infiltration and incorporation in neo-vessels, enhance the expression and function of pro-angiogenic factors, such as SDF-1, vascular endothelial growth factor and matrix metalloprotein-9, and activate cell signals involved in angiogenesis, such as proliferating cell nuclear antigen, protein kinase B (Akt), extracellular regulated protein kinases and mammalian target of rapamycin, in ischaemic tissue. Moreover, P2G can attenuate fibrotic remodelling to facilitate the recovery of ischaemic tissue. The capability of P2G in direct augmenting ischaemic environment for angiogenesis suggests that it is a potential candidate for the therapy of ischaemia diseases.
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.|Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA.|Chinese-American Pediatric Research Institute at the First Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yan
authors.affiliation: Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA.|School of Biomedicine, Chengdu Medical College, Chengdu, Sichuan, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Dai
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: He
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ling
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.
authors.forename: Minglong
authors.initials: M
authors.lastname: Shao
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Geriatric Medicine, the first hospital of Jilin university, Changchun, Jilin, China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.|Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA.|Chinese-American Pediatric Research Institute at the First Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Chashan University-town, Wenzhou, Zhejiang, China.|Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA.|Chinese-American Pediatric Research Institute at the First Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yi
authors.identifier: 0000-0002-9798-6237
authors.initials: Y
authors.lastname: Tan
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000378:metabolism; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D010455:Peptides; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9
keywords: AMD3100; P2G; angiogenesis; endothelial progenitor cells