title: Endothelial, but not smooth muscle, peroxisome proliferator-activated receptor β/δ regulates vascular permeability and anaphylaxis.
abstract: BACKGROUND
  Remodeling of quiescent vessels with increases in permeability, vasodilatation, and edema are hallmarks of inflammatory disorders. Factors involved in this type of remodeling represent potential therapeutic targets.
  
  
  OBJECTIVE
  We investigated whether the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) β/δ, a regulator of metabolism, fibrosis, and skin homeostasis, is involved in regulation of this type of remodeling.
  
  
  METHODS
  Wild-type and various Pparb/d mutant mice were used to monitor dermal acute vascular hyperpermeability (AVH) and passive systemic anaphylaxis-induced hypothermia and edema. PPARβ/δ-dependent kinase activation and remodeling of endothelial cell-cell junctions were addressed by using human endothelial cells.
  
  
  RESULTS
  AVH and dilatation of dermal microvessels stimulated by vascular endothelial growth factor A, histamine, and thrombin are severely compromised in PPARβ/δ-deficient mice. Selective deletion of the Pparb/d-encoding gene in endothelial cells in vivo similarly limits dermal AVH and vasodilatation, providing evidence that endothelial PPARβ/δ is the major player in regulating acute dermal microvessel remodeling. Furthermore, endothelial PPARβ/δ regulatory functions are not restricted to the skin vasculature because its deletion in the endothelium, but not in smooth muscle cells, also leads to reduced systemic anaphylaxis, the most severe form of allergic reaction, in which an acute vascular response plays a key role. PPARβ/δ-dependent AVH activation likely involves the activation of mitogen-activated protein kinase and Akt pathways and leads to downstream destabilization of endothelial cell-cell junctions.
  
  
  CONCLUSIONS
  These results unveil not only a novel function of PPARβ/δ as a direct regulator of acute vessel permeability and dilatation but also provide evidence that antagonizing PPARβ/δ represents an important strategy to consider for moderating diseases with altered endothelial integrity, such as acute inflammatory and allergic disorders.
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Wawrzyniak
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Pich
authors.affiliation: INSERM U1011, Université Lille 2, Institut Pasteur de Lille, Lille, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gross
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Schütz
authors.affiliation: INSERM U1011, Université Lille 2, Institut Pasteur de Lille, Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fleury
authors.affiliation: INSERM U1011, Université Lille 2, Institut Pasteur de Lille, Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Quemener
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Sgandurra
authors.affiliation: INSERM U1011, Université Lille 2, Institut Pasteur de Lille, Lille, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouchaert
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Moret
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mury
authors.affiliation: INSERM U1011, Université Lille 2, Institut Pasteur de Lille, Lille, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Rommens
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Mottaz
authors.affiliation: INSERM U1011, Université Lille 2, Institut Pasteur de Lille, Lille, France. Electronic address: david.dombrowicz@pasteur-lille.fr.
authors.forename: David
authors.initials: D
authors.lastname: Dombrowicz
authors.affiliation: Center for Integrative genomics, University of Lausanne, Lausanne, Switzerland. Electronic address: liliane.michalik@unil.ch.
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
mesh_terms: D000707:Anaphylaxis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology*; D004487:Edema / Q000235:genetics / Q000276:immunology / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006632:Histamine / Q000494:pharmacology; D007035:Hypothermia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007365:Intercellular Junctions / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D047494:PPAR delta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D048068:PPAR-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013917:Thrombin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D006632:Histamine; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin
keywords: Peroxisome proliferator-activated receptor β/δ; anaphylaxis; endothelium; smooth muscle cells; vascular permeability