title: Essential role of Apelin signaling during lymphatic development in zebrafish.
abstract: OBJECTIVE
  Apelin and its cognate receptor Aplnr/Apj are essential for diverse biological processes. However, the function of Apelin signaling in lymphatic development remains to be identified, despite the preferential expression of Apelin and Aplnr within developing blood and lymphatic endothelial cells in vertebrates. In this report, we aim to delineate the functions of Apelin signaling during lymphatic development.
  
  
  RESULTS
  We investigated the functions of Apelin signaling during lymphatic development using zebrafish embryos and found that attenuation of Apelin signaling substantially decreased the formation of the parachordal vessel and the number of lymphatic endothelial cells within the developing thoracic duct, indicating an essential role of Apelin signaling during the early phase of lymphatic development. Mechanistically, we found that abrogation of Apelin signaling selectively attenuates lymphatic endothelial serine-threonine kinase Akt 1/2 phosphorylation without affecting the phosphorylation status of extracellular signal-regulated kinase 1/2. Moreover, lymphatic abnormalities caused by the reduction of Apelin signaling were significantly exacerbated by the concomitant partial inhibition of serine-threonine kinase Akt/protein kinase B signaling. Apelin and vascular endothelial growth factor-C (VEGF-C) signaling provide a nonredundant activation of serine-threonine kinase Akt/protein kinase B during lymphatic development because overexpression of VEGF-C or apelin was unable to rescue the lymphatic defects caused by the lack of Apelin or VEGF-C, respectively.
  
  
  CONCLUSIONS
  Taken together, our data present compelling evidence suggesting that Apelin signaling regulates lymphatic development by promoting serine-threonine kinase Akt/protein kinase B activity in a VEGF-C/VEGF receptor 3-independent manner during zebrafish embryogenesis.
authors: From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (J.-D.K., Y.K., I.P., H.K., J.W., H.P., E.N., H.J.C., S.-W.J.); Department of Life Systems, Sookmyung Women's University, Seoul, Korea (J.K.); and Department of Medicine, Stanford University, School of Medicine, CA (S.G.R.).
authors: Jun-Dae
authors: JD
authors: Kim
authors: Yujung
authors: Y
authors: Kang
authors: Jongmin
authors: J
authors: Kim
authors: Irinna
authors: I
authors: Papangeli
authors: Hyeseon
authors: H
authors: Kang
authors: Jingxia
authors: J
authors: Wu
authors: Hyekyung
authors: H
authors: Park
authors: Emily
authors: E
authors: Nadelmann
authors: Stanley G
authors: SG
authors: Rockson
authors: Hyung J
authors: HJ
authors: Chun
authors: Suk-Won
authors: SW
authors: Jin
mesh_terms: D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000196:embryology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D042583:Lymphangiogenesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013897:Thoracic Duct / Q000196:embryology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D042582:Vascular Endothelial Growth Factor C; D029961:Zebrafish Proteins; C519093:apelin receptor, zebrafish; C519092:apln protein, zebrafish; C493178:vascular endothelial growth factor C, zebrafish; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: APJ receptor; apelin protein; lymphatic vessels; zebrafish