title: Stromal cell-derived factor-1α/C-X-C chemokine receptor type 4 axis promotes endothelial cell barrier integrity via phosphoinositide 3-kinase and Rac1 activation.
abstract: OBJECTIVE
  Although stromal cell-derived factor (SDF)-1αis well known to modulate the mobilization of hematopoietic stem cells and endothelial progenitor cells, its effects on some pre-existing vascular functions remain unknown. We have investigated here the role of SDF-1αsignaling in endothelial barrier function.
  
  
  RESULTS
  Treatment with SDF-1α elevated transendothelial electrical resistance and inhibited the dextran hyperpermeability elicited by thrombin in bovine aortic endothelial cells, both indicating an increase in endothelial barrier function. SDF-1α binds to 2 receptors, C-X-C chemokine receptor types 4 and 7 (CXCR4 and CXCR7). Pretreatment with a CXCR4 antagonist or CXCR4 gene depletion by small interfering RNA (siRNA) eliminated SDF-1α-induced endothelial barrier enhancement. In contrast, CXCR7 antagonist or CXCR7 gene depletion by siRNA did not influence SDF-1α-induced barrier enhancement. Pretreatment with a Gi-protein inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, or PI3K p110γsubunit gene depletion by siRNA also inhibited SDF-1α-induced barrier enhancement significantly. Western blot analysis revealed that SDF-1α phosphorylated Akt(Ser473) in endothelial cells, suggesting PI3K activation. Immunostaining showed that treatment with SDF-1αformed a cortical actin rim, which was accompanied by Rac1 activation. In vivo, SDF-1αinhibited croton oil-induced vascular leakage indexed by dye extravasation, which is attenuated by a pretreatment with a CXCR4 antagonist.
  
  
  CONCLUSIONS
  We have identified SDF-1α as a novel suppressor of endothelial permeability. Specifically, SDF-1α stimulates the CXCR4/PI3K/Rac1 signaling pathway and the subsequent cytoskeletal rearrangement.
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Sato
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Kida
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Omori
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.affiliation: From the Departments of Animal Radiology (K.K., K.O., T.M.) and Veterinary Pharmacology (K.S., T.K., M.H., H.O.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan. amurata@mail.ecc.u-tokyo.ac.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; C107953:RAC1 protein, human; D019718:Receptors, CXCR4; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein
keywords: CXCR4 receptor; SDF-1α; endothelial cells