title: CXCR7 upregulation is required for early endothelial progenitor cell-mediated endothelial repair in patients with hypertension.
abstract: Dysfunction of early endothelial progenitor cells (EPCs) is responsible for impaired endothelial repair capacity after arterial injury in patients with hypertension. Here, we hypothesized that diminished signaling of CXC chemokine receptor 7 (CXCR7) contributes to the reduced EPC functions, and enhanced CXCR7 expression restores the capacities of EPCs from hypertensive patients. CXCR7 expression of EPCs from hypertensive patients was significantly reduced when compared with that from healthy subjects. Meanwhile, the phosphorylation of p38 mitogen-activated protein kinase, a downstream signaling of CXCR7, was elevated, which increased cleaved caspase-3 level of EPCs. CXCR7 gene transfer augmented CXCR7 expression and decreased the phosphorylation of p38 mitogen-activated protein kinase, which was paralleled to EPC functional upregulation of in vitro adhesion, antiapoptosis activities, and in vivo re-endothelialization capacity in a nude mouse model of carotid artery injury. The enhanced in vitro and in vivo functions of EPCs were markedly inhibited by neutralizing monoclonal antibody against CXCR7, which was blocked by p38 mitogen-activated protein kinase inhibitor SB203580. Downregulation of cleaved caspase-3 level induced by CXCR7 gene transfer or SB203580 pretreatment improved EPC functions. Furthermore, we found that lercanidipine, a dihydropyridine calcium channel antagonist, enhanced CXCR7 expression and facilitated in vitro and in vivo functions of EPCs. Our study demonstrated for the first time that diminished CXCR7 signal at least partially contributes to the reduced in vitro functions and in vivo re-endothelialization capacity of EPCs from hypertensive patients. Upregulation of CXCR7 expression induced by gene transfer or lercanidipine treatment may be a novel therapeutic target for increased endothelial repair capacity in hypertension.
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China. taojungz@yahoo.com or wangy68@mail.sysu.edu.cn.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Su
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cao
authors.forename: Shi-Yue
authors.initials: SY
authors.lastname: Xu
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Xia
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Xie
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Bing-Bo
authors.initials: BB
authors.lastname: Yu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Tao
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology
chemical_list: C501896:ACKR3 protein, human; D000959:Antihypertensive Agents; D004095:Dihydropyridines; D054387:Receptors, CXCR; C505407:CASP3 protein, human; D053148:Caspase 3; C060343:lercanidipine
keywords: CXCR7 protein; endothelial progenitor cells; endothelial repair; gene transfer techniques; human; hypertension; lercanidipine; p38 mitogen-activated protein kinases