title: BMP4/Id2 signaling pathway is a novel therapeutic target for late outgrowth endothelial progenitor cell-mediated endothelial injury repair.
abstract: BACKGROUND
  Endothelial progenitor cells (EPCs) play a pivotal role in endothelial repair following artery injury, however, the molecular mechanism of late outgrowth EPCs (LEPCs) in endothelial repair remained to be studied. Bone morphogenetic protein 4 (BMP4) is involved in vascular injury-mediated mobilization and homing of LEPCs. Here, we investigated the influence of BMP4-modified signaling pathway in LEPC-related endothelial repair of human and underlying molecular mechanism.
  
  
  RESULTS
  In vitro, after a 28day culture, human LEPCs were pretreated with different concentrations of recombinant BMP4 (0, 10, 50, or 100ng/mL), which markedly augmented the migration and adhesion in vitro and demonstrated a significantly accelerated in vivo endothelial repair capacity of human LEPCs after transplantation into nude mice with carotid artery denudation injury. Moreover, the main Id gene (Id2), a well-characterized down-streaming target of BMP4, upregulated in LEPCs incubated with recombinant BMP4. The BMP4-induced enhancement in in vitro functional activities and in vivo endothelial repair capacity of human LEPCs were abolished by pretreatment with BMP antagonist Noggin or shRNA-mediated knockdown of BMP4 expression. Furthermore, BMP4 gene transfer remarkably activated BMP4-mediated signaling pathway and facilitated therapeutic endothelial repair capacity of LEPCs, and the improved functional activities of human LEPCs could be inhibited by Noggin.
  
  
  CONCLUSIONS
  Thus, the present study demonstrates for the first time that BMP4-related signaling pathway is essential with endothelial repair capacity of LEPCs in human. The upregulation of BMP4-modified signaling pathway in human LEPCs may be a novel therapeutic strategy for endothelial repair after injury.
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Xia
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Liang
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Su
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China; Department of Cardiology, Shiyan Taihe Hospital, Hubei University of Medicine, China.
authors.forename: Xinzhu
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shiyan Taihe Hospital, Hubei University of Medicine, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Cardiology, The Fifth Affiliated Hospital, Sun Yat-Sen University, China. Electronic address: linxiufang126_@126.com.
authors.forename: Xiu-Fang
authors.initials: XF
authors.lastname: Lin
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China. Electronic address: taojungz123@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Tao
mesh_terms: D000328:Adult; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology*; D002448:Cell Adhesion; D002465:Cell Movement; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology; D055815:Young Adult
chemical_list: D055415:Bone Morphogenetic Protein 4; D051797:Inhibitor of Differentiation Protein 2
keywords: Bone morphogenetic protein 4; Cell therapy; Endothelial injury; Endothelial repair; Late outgrowth endothelial progenitor cells