title: Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage.
abstract: Altered pulmonary hemodynamics and fluid flow-induced high shear stress (HSS) are characteristic hallmarks in the pathogenesis of pulmonary arterial hypertension (PAH). However, the contribution of HSS to cellular and vascular alterations in PAH is unclear.
  
  
  
  We hypothesize that failing shear adaptation is an essential part of the endothelial dysfunction in all forms of PAH and tested whether microvascular endothelial cells (MVECs) or pulmonary arterial endothelial cells (PAECs) from lungs of patients with PAH adapt to HSS and if the shear defect partakes in vascular remodeling in vivo.
  
  
  
  PAH MVEC (n = 7) and PAH PAEC (n = 3) morphology, function, protein, and gene expressions were compared with control MVEC (n = 8) under static culture conditions and after 24, 72, and 120 hours of HSS.
  
  
  
  PAH MVEC showed a significantly delayed morphological shear adaptation (P = 0.03) and evidence of cell injury at sites of nonuniform shear profiles that are critical loci for vascular remodeling in PAH. In clear contrast, PAEC isolated from the same PAH lungs showed no impairments. PAH MVEC gene expression and transcriptional shear activation were not altered but showed significant decreased protein levels (P = 0.02) and disturbed interendothelial localization of the shear sensor platelet endothelial cell adhesion molecule-1 (PECAM-1). The decreased PECAM-1 levels were caused by caspase-mediated cytoplasmic cleavage but not increased cell apoptosis. Caspase blockade stabilized PECAM-1 levels, restored endothelial shear responsiveness in vitro, and attenuated occlusive vascular remodeling in chronically hypoxic Sugen5416-treated rats modeling severe PAH.
  
  
  
  Delayed shear adaptation, which promotes shear-induced endothelial injury, is a newly identified dysfunction specific to the microvascular endothelium in PAH. The shear response is normalized on stabilization of PECAM-1, which reverses intimal remodeling in vivo.
authors.affiliation: 1 Department of Pulmonology.|2 Department of Physiology.
authors.forename: Robert
authors.initials: R
authors.lastname: Szulcek
authors.affiliation: 1 Department of Pulmonology.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Happé
authors.affiliation: 1 Department of Pulmonology.|2 Department of Physiology.
authors.forename: Nina
authors.initials: N
authors.lastname: Rol
authors.affiliation: 3 Department of Molecular Cell Biology and Immunology.
authors.forename: Ruud D
authors.initials: RD
authors.lastname: Fontijn
authors.affiliation: 4 Department of Surgery, and.
authors.forename: Chris
authors.initials: C
authors.lastname: Dickhoff
authors.affiliation: 4 Department of Surgery, and.
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Hartemink
authors.affiliation: 5 Department of Pathology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Grünberg
authors.affiliation: 6 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|7 Université Paris-Sud, School of Médecine, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Ly
authors.initials: L
authors.lastname: Tu
authors.affiliation: 8 Department of Pathology and Medical Biology, and.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: 9 Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; and.
authors.forename: George D
authors.initials: GD
authors.lastname: Nossent
authors.affiliation: 4 Department of Surgery, and.
authors.forename: Marinus A
authors.initials: MA
authors.lastname: Paul
authors.affiliation: 3 Department of Molecular Cell Biology and Immunology.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Leyen
authors.affiliation: 3 Department of Molecular Cell Biology and Immunology.
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Horrevoets
authors.affiliation: 1 Department of Pulmonology.
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
authors.affiliation: 6 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|7 Université Paris-Sud, School of Médecine, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.affiliation: 10 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.affiliation: 1 Department of Pulmonology.
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: 2 Department of Physiology.
authors.forename: Geerten P
authors.initials: GP
authors.lastname: van Nieuw Amerongen
authors.affiliation: 1 Department of Pulmonology.
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Bogaard
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D055806:Microvessels / Q000378:metabolism / Q000503:physiopathology*; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D066253:Vascular Remodeling / Q000502:physiology*; D055815:Young Adult
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1
keywords: endothelial cell; microcirculation; molecular biology; pulmonary arterial hypertension; shear stress