title: Apelin enhances cardiac neovascularization after myocardial infarction by recruiting aplnr+ circulating cells.
abstract: BACKGROUND
  Neovascularization stimulated by local or recruited stem cells after ischemia is a key process that salvages damaged tissue and shows similarities with embryonic vascularization. Apelin receptor (Aplnr) and its endogenous ligand apelin play an important role in cardiovascular development. However, the role of apelin signaling in stem cell recruitment after ischemia is unknown.
  
  
  OBJECTIVE
  To investigate the role of apelin signaling in recruitment after ischemia.
  
  
  RESULTS
  Aplnr was specifically expressed in circulating cKit+/Flk1+ cells but not in circulating Sca1+/Flk1+ and Lin+ cells. cKit+/Flk1+/Aplnr+ cells increased significantly early after myocardial ischemia but not after hind limb ischemia, indicative of an important role for apelin/Aplnr in cell recruitment during the nascent biological repair response after myocardial damage. In line with this finding, apelin expression was upregulated in the infarcted myocardium. Injection of apelin into the ischemic myocardium resulted in accelerated and increased recruitment of cKit+/Flk1+/Aplnr+ cells to the heart. Recruited Aplnr+/cKit+/Flk1+ cells promoted neovascularization in the peri-infarct area by paracrine activity rather than active transdifferentiation, resulting into cardioprotection as indicated by diminished scar formation and improved residual cardiac function. Aplnr knockdown in the bone marrow resulted in aggravation of myocardial ischemia-associated damage, which could not be rescued by apelin.
  
  
  CONCLUSIONS
  We conclude that apelin functions as a new and potent chemoattractant for circulating cKit+/Flk1+/Aplnr+ cells during early myocardial repair, providing myocardial protection against ischemic damage by improving neovascularization via paracine action.
authors: FESC, Molecular Cardiology Laboratory, Ee2389a, Thoraxcenter Rotterdam, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 GE Rotterdam, The Netherlands.
authors: Dennie
authors: D
authors: Tempel
authors: Martine
authors: M
authors: de Boer
authors: Elza D
authors: ED
authors: van Deel
authors: Remco A
authors: RA
authors: Haasdijk
authors: Dirk J
authors: DJ
authors: Duncker
authors: Caroline
authors: C
authors: Cheng
authors: Stefan
authors: S
authors: Schulte-Merker
authors: Henricus J
authors: HJ
authors: Duckers
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000502:physiology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D015552:Injections, Intralesional; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2