title: Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin.
abstract: Pulmonary edema occurs in settings of acute lung injury, in diseases, such as pneumonia, and in acute respiratory distress syndrome. The lung interendothelial junctions are maintained in part by vascular endothelial (VE)-cadherin, an adherens junction protein, and its surface expression is regulated by endocytic trafficking. The Rab family of small GTPases are regulators of endocytic trafficking. The key trafficking pathways are regulated by Rab4, -7, and -9. Rab4 regulates the recycling of endosomes to the cell surface through a rapid-shuttle process, whereas Rab7 and -9 regulate trafficking to the late endosome/lysosome for degradation or from the trans-Golgi network to the late endosome, respectively. We recently demonstrated a role for the endosomal adaptor protein, p18, in regulation of the pulmonary endothelium through enhanced recycling of VE-cadherin to adherens junction. Thus, we hypothesized that Rab4, -7, and -9 regulate pulmonary endothelial barrier function through modulating trafficking of VE-cadherin-positive endosomes. We used Rab mutants with varying activities and associations to the endosome to study endothelial barrier function in vitro and in vivo. Our study demonstrates a key role for Rab4 activation and Rab9 inhibition in regulation of vascular permeability through enhanced VE-cadherin expression at the interendothelial junction. We further showed that endothelial barrier function mediated through Rab4 is dependent on extracellular signal-regulated kinase phosphorylation and activity. Thus, we demonstrate that Rab4 and -9 regulate VE-cadherin levels at the cell surface to modulate the pulmonary endothelium through extracellular signal-regulated kinase-dependent and -independent pathways, respectively. We propose that regulating select Rab GTPases represents novel therapeutic strategies for patients suffering with acute respiratory distress syndrome.
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Havovi
authors.identifier: 0000-0002-8549-7583
authors.initials: H
authors.lastname: Chichger
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Julie
authors.initials: J
authors.lastname: Braza
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Huetran
authors.initials: H
authors.lastname: Duong
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Boni
authors.affiliation: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Elizabeth O
authors.identifier: 0000-0002-3207-5301
authors.initials: EO
authors.lastname: Harrington
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D021381:Protein Transport / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D048049:Extracellular Signal-Regulated MAP Kinases; D008070:Lipopolysaccharides; D020691:rab GTP-Binding Proteins; D000099152:Cadherin 5
keywords: Rab GTPase; acute respiratory distress syndrome; endocytosis; endothelium; vascular endothelial-cadherin