title: Bone Morphogenetic Protein-Modulator BMPER Regulates Endothelial Barrier Function.
abstract: The endothelium serves as a selective barrier and controls the exchange of nutrients, hormones, and leukocytes between blood and tissues. Molecular mechanisms contributing to the pathogenesis of endothelial barrier dysfunction remain incompletely understood. Accumulating evidence implicates bone morphogenetic protein (BMP)-modulator BMPER as a key regulator in endothelial biology. Herein, we analyze the impact of BMPER in the control of endothelial barrier function. To assess the role of BMPER in vascular barrier function in mice, we measured the leakage of Evans blue dye from blood into interstitial lung tissue. BMPER+/-mice exhibited a significantly higher degree of vascular leak compared with wild-type siblings. In accordance with our in vivo observation, siRNA-based BMPER knockdown in human umbilical endothelial cells increased endothelial permeability measured by FITC-dextran passage in transwell assays. Mechanistically, BMPER knockdown reduced the expression of VE-cadherin, a pivotal component of endothelial adherens junctions. Conversely, recombinant human BMPER protein upregulated VE-cadherin protein levels and improved endothelial barrier function in transwell assays. The effects of BMPER knockdown on VE-cadherin expression and endothelial permeability were induced by enhanced BMP activity. Supporting this notion, activation of BMP4-Smad-Id1 signaling reduced VE-cadherin levels and impaired endothelial barrier function in vitro. In vivo, Evans blue dye accumulation was higher in the lungs of BMP4-treated C57BL/6 mice compared to controls indicating that BMP4 increased vascular permeability. High levels of BMPER antagonized BMP4-Smad5-Id1 signaling and prevented BMP4-induced downregulation of VE-cadherin and endothelial leakage, suggesting that BMPER exerts anti-BMP effects and restores endothelial barrier function. Taken together, this data demonstrates that BMPER-modulated BMP pathway activity regulates VE-cadherin expression and vascular barrier function.
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany. thomas.helbing@universitaets-herzzentrum.de.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany. thomas.helbing@universitaets-herzzentrum.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helbing
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Wiltgen
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hornstein
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Elena Z
authors.initials: EZ
authors.lastname: Brauers
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Linus
authors.initials: L
authors.lastname: Arnold
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Esser
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Diehl
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grundmann
authors.affiliation: Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Department of Emergency Medicine, University Hospital of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fink
authors.affiliation: McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.|New York-Presbyterian Hospital, New York City, NY, 10065, USA.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: Department of Cardiology and Angiology, Heart Center Freiburg University, Hugstetter Strasse 55, 79106, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000008:administration & dosage / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D015820:Cadherins; D002352:Carrier Proteins; D034741:RNA, Small Interfering; D000099152:Cadherin 5; C525809:BMP4 protein, human; C476724:BMPER protein, human
keywords: BMP4; BMPER; Smad; VE-cadherin; endothelial barrier function