title: Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis.
abstract: Apelin has been identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. This peptide exerts a variety of cardiovascular effects and particularly acts as an activator of angiogenesis. Importantly, hypoxia has been reported to regulate apelin expression but the molecular mechanism underlying hypoxia-induced apelin expression and the relationship with the physiological response of the apelin/APJ system are still not established. Here, we demonstrate that apelin expression is induced by hypoxia in cultured endothelial and vascular smooth muscle cells as well as in lung from mice exposed to acute hypoxia. Transient transfection experiments show that hypoxia-inducible transcriptional activation of apelin requires an intact hypoxia-responsive element (+813/+826) located within the first intron of the human apelin gene. Chromatin immunoprecipitation assay reveals that hypoxia-inducible factor-1alpha binds to the endogenous hypoxia-responsive element site of the apelin gene. Moreover, overexpression of hypoxia-inducible factor-1alpha increases the transcriptional activity of a reporter construct containing this hypoxia-responsive element, whereas small interfering RNA-mediated hypoxia-inducible factor-1alpha knockdown abolishes hypoxia-induced apelin expression. Finally, microinterfering RNA-mediated apelin or APJ receptor knockdown inhibits both hypoxia-induced endothelial cell proliferation in vitro and hypoxia-induced vessel regeneration in the caudal fin regeneration of Fli-1 transgenic zebrafish. The hypoxia-induced apelin expression may, thus, provide a new mechanism involved in adaptive physiological and pathophysiological response of vascular cells to low oxygen level.
authors.affiliation: INSERM UMRS 525, Université Pierre et Marie Curie, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Eyries
authors.forename: Géraldine
authors.initials: G
authors.lastname: Siegfried
authors.forename: Mariana
authors.initials: M
authors.lastname: Ciumas
authors.forename: Kevin
authors.initials: K
authors.lastname: Montagne
authors.forename: Monique
authors.initials: M
authors.lastname: Agrapart
authors.forename: Franck
authors.initials: F
authors.lastname: Lebrin
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
mesh_terms: D054392:Adipokines; D000595:Amino Acid Sequence; D000818:Animals; D000073861:Apelin; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012038:Regeneration / Q000276:immunology*; D014162:Transfection; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C115436:APLN protein, human; D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; C498579:Apln protein, rat; D002352:Carrier Proteins; D018925:Chemokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D029961:Zebrafish Proteins; C519092:apln protein, zebrafish