title: Age-related decline in reendothelialization capacity of human endothelial progenitor cells is restored by shear stress.
abstract: Aging is associated with dysfunction of endothelial progenitor cells (EPCs), and shear stress has a beneficial impact on EPC function; however, the effects of aging and shear stress on the endothelial repair capacity of EPCs after arterial injury have not been reported. Here we investigated the influence of aging and shear stress on the reendothelialization capacity of human EPCs and the related molecular mechanism. Compared with EPCs isolated from young subjects, EPCs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced reendothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury. Shear stress pretreatment enhances the migration, adhesion, and reendothelialization capacity in both young and elderly EPCs; however, it was to a greater extent in EPCs from the elderly. Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1-induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs. Shear stress treatment upregulated CXCR4 expression and phosphorylation and, importantly, restored the stromal cell-derived factor 1/CXCR4-dependent Janus kinase 2 phosphorylation in the elderly EPCs. Furthermore, short hairpin RNA-mediated knockdown of CXCR4 expression or pretreatment with Janus kinase 2 inhibitor diminished the enhancement in the migration, adhesion, and reendothelialization capacity of the elderly EPCs from shear stress treatments. Thus, our study demonstrates that upregulation of the CXCR4/Janus kinase 2 pathway by shear stress contributes to the enhanced reendothelialization capacity of EPCs from elderly men.
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Wen Hao
authors.initials: WH
authors.lastname: Xia
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Shi Yue
authors.initials: SY
authors.lastname: Xu
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Yan Xia
authors.initials: YX
authors.lastname: Qiu
authors.forename: Xin Tao
authors.initials: XT
authors.lastname: Shuai
authors.forename: Jun
authors.initials: J
authors.lastname: Tao
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D020212:Carotid Artery Injuries / Q000503:physiopathology / Q000601:surgery; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D013314:Stress, Mechanical; D014183:Transplantation, Heterologous
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D053614:Janus Kinase 2