title: Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function.
abstract: OBJECTIVE
  Vascular endothelial (VE)-cadherin is the predominant component of endothelial adherens junctions essential for cell-cell adhesion and formation of the vascular barrier. Endocytic recycling is an important mechanism for maintaining the expression of cell surface membrane proteins. However, little is known about the molecular mechanism of VE-cadherin recycling and its role in maintenance of vascular integrity.
  
  
  RESULTS
  Using calcium-switch assay, confocal imaging, cell surface biotinylation, and flow cytometry, we showed that VE-cadherin recycling required Ras-related proteins in brain (Rab)11a and Rab11 family-interacting protein 2. Yeast 2-hybrid assay and coimmunoprecipitation demonstrated that direct interaction of VE-cadherin with family-interacting protein 2 (at aa 453-484) formed a ternary complex with Rab11a in human endothelial cells. Silencing of Rab11a or Rab11 family-interacting protein 2 in endothelial cells prevented VE-cadherin recycling and VE-cadherin expression at endothelial plasma membrane. Furthermore, inactivation of Rab11a signaling blocked junctional reannealing after vascular inflammation. Selective knockdown of Rab11a in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide or polymicrobial sepsis.
  
  
  CONCLUSIONS
  Rab11a/Rab11 family-interacting protein 2-mediated VE-cadherin recycling is required for formation of adherens junctions and restoration of VE barrier integrity and hence a potential target for clinical intervention in inflammatory disease.
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yan
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Zhen-Guo
authors.initials: ZG
authors.lastname: Wang
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Nava
authors.initials: N
authors.lastname: Segev
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Sanyuan
authors.initials: S
authors.lastname: Hu
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Randal O
authors.initials: RO
authors.lastname: Dull
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Meihong
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.).
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: From the Departments of Anesthesiology (Z.Y., Z.-G.W., R.D.M., R.O.D., M.Z., G.H.), Pharmacology (Z.Y., R.D.M., A.B.M., G.H.), and Biochemistry and Molecular Genetics (N.S.), University of Illinois College of Medicine, Chicago; and Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China (Z.Y., S.H.). gchu@uic.edu.
authors.forename: Guochang
authors.initials: G
authors.lastname: Hu
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004705:Endocytosis; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D019446:Endotoxemia / Q000378:metabolism / Q000382:microbiology; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000098:blood supply*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D011654:Pulmonary Edema / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D034622:RNA Interference; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D002352:Carrier Proteins; D008565:Membrane Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; D000099152:Cadherin 5; C463963:RAB11FIP2 protein, human
keywords: adherens junctions; inflammation; membrane protein; permeability; sepsis