Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function

Zhibo Yan, Zhen Guo Wang, Nava Segev, Sanyuan Hu, Richard D. Minshall, Randal O. Dull, Meihong Zhang, Asrar B. Malik, Guochang Hu

Research output: Contribution to journalArticle

25 Scopus citations

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. Approach and 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.

Original languageEnglish (US)
Pages (from-to)339-349
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Keywords

  • Adherens junctions
  • Inflammation
  • Membrane protein
  • Permeability
  • Sepsis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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