N-cadherin signaling via Trio assembles adherens junctions to restrict endothelial permeability

J Cell Biol. 2019 Jan 7;218(1):299-316. doi: 10.1083/jcb.201802076. Epub 2018 Nov 21.

Abstract

Vascular endothelial (VE)-cadherin forms homotypic adherens junctions (AJs) in the endothelium, whereas N-cadherin forms heterotypic adhesion between endothelial cells and surrounding vascular smooth muscle cells and pericytes. Here we addressed the question whether both cadherin adhesion complexes communicate through intracellular signaling and contribute to the integrity of the endothelial barrier. We demonstrated that deletion of N-cadherin (Cdh2) in either endothelial cells or pericytes increases junctional endothelial permeability in lung and brain secondary to reduced accumulation of VE-cadherin at AJs. N-cadherin functions by increasing the rate of VE-cadherin recruitment to AJs and induces the assembly of VE-cadherin junctions. We identified the dual Rac1/RhoA Rho guanine nucleotide exchange factor (GEF) Trio as a critical component of the N-cadherin adhesion complex, which activates both Rac1 and RhoA signaling pathways at AJs. Trio GEF1-mediated Rac1 activation induces the recruitment of VE-cadherin to AJs, whereas Trio GEF2-mediated RhoA activation increases intracellular tension and reinforces Rac1 activation to promote assembly of VE-cadherin junctions and thereby establish the characteristic restrictive endothelial barrier.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / metabolism*
  • Adherens Junctions / ultrastructure
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Aorta / cytology
  • Aorta / metabolism
  • Brain / cytology
  • Brain / metabolism
  • Cadherins / deficiency
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Endothelial Cells / metabolism*
  • Endothelial Cells / ultrastructure
  • Female
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Lung / cytology
  • Lung / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Pericytes / metabolism*
  • Pericytes / ultrastructure
  • Permeability
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Primary Cell Culture
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism
  • rhoA GTP-Binding Protein

Substances

  • Antigens, CD
  • Cadherins
  • Cdh2 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Neuropeptides
  • Phosphoproteins
  • Rac1 protein, mouse
  • Trio protein, mouse
  • cadherin 5
  • Protein Serine-Threonine Kinases
  • RhoA protein, mouse
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein