title: Sphingosine-1-phosphate receptor-1 controls venous endothelial barrier integrity in zebrafish.
abstract: OBJECTIVE
  Endothelial sphingosine-1-phosphate (S1P) receptor-1 (S1P(1)) affects different vascular functions, including blood vessel maturation and permeability. Here, we characterized the role of the zS1P(1) ortholog in vascular development in zebrafish.
  
  
  RESULTS
  zS1P(1) is expressed in dorsal aorta and posterior cardinal vein of zebrafish embryos at 24 to 30 hours postfertilization. zS1P(1) downregulation by antisense morpholino oligonucleotide injection causes early pericardial edema, lack of blood circulation, alterations of posterior cardinal vein structure, and late generalized edema. Also, zS1P(1) morphants are characterized by downregulation of vascular endothelial cadherin (VE-cadherin) and Eph receptor EphB4a expression and by disorganization of zonula occludens 1 junctions in posterior cardinal vein endothelium, with no alterations of dorsal aorta endothelium. VE-cadherin knockdown results in similar vascular alterations, whereas VE-cadherin overexpression is sufficient to rescue venous vascular integrity defects and EphB4a downregulation in zS1P(1) morphants. Finally, S1P(1) small interfering RNA transfection and the S1P(1) antagonist (R)-3-amino-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146) cause EPHB4 receptor down-modulation in human umbilical vein endothelial cells and the assembly of zonula occludens 1 intercellular contacts is prevented by the EPHB4 antagonist TNYL-RAW peptide in these cells.
  
  
  CONCLUSIONS
  The data demonstrate a nonredundant role of zS1P(1) in the regulation of venous endothelial barrier in zebrafish and identify a S1P(1)/VE-cadherin/EphB4a genetic pathway that controls venous vascular integrity.
authors: Department of Biomedical Sciences and Biotechnology, Unit of General Pathology and Immunology, School of Medicine, University of Brescia, Italy.
authors: Chiara
authors: C
authors: Tobia
authors: Paola
authors: P
authors: Chiodelli
authors: Stefania
authors: S
authors: Nicoli
authors: Patrizia
authors: P
authors: Dell'era
authors: Simone
authors: S
authors: Buraschi
authors: Stefania
authors: S
authors: Mitola
authors: Efrem
authors: E
authors: Foglia
authors: Pieter B
authors: PB
authors: van Loenen
authors: Astrid E
authors: AE
authors: Alewijnse
authors: Marco
authors: M
authors: Presta
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000378:metabolism; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D060172:Morpholinos / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D034622:RNA Interference; D036224:Receptor, EphB4 / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D019108:Tight Junctions / Q000378:metabolism; D014162:Transfection; D014680:Veins / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5
chemical_list: D000813:Anilides; D015703:Antigens, CD; D015820:Cadherins; D049452:Green Fluorescent Proteins; D008565:Membrane Proteins; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D063065:Organophosphonates; D010750:Phosphoproteins; D036224:Receptor, EphB4; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D029961:Zebrafish Proteins; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5; C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; C477362:S1PR1 protein, human; C569042:TJP1 protein, human; C485184:enhanced green fluorescent protein