JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function

Circ Res. 2020 Sep 25;127(8):1056-1073. doi: 10.1161/CIRCRESAHA.120.316742. Epub 2020 Jul 15.


Rationale: Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumor growth. JAM-A (junctional adhesion molecule A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barrier function, although how this is accomplished remains elusive.

Objective: We aimed to understand the molecular mechanisms through which JAM-A expression regulates tight junction organization to control endothelial permeability, with potential implications under pathological conditions.

Methods and results: Genetic deletion of JAM-A in mice significantly increased vascular permeability. This was associated with significantly decreased expression of claudin-5 in the vasculature of various tissues, including brain and lung. We observed that C/EBP-α (CCAAT/enhancer-binding protein-α) can act as a transcription factor to trigger the expression of claudin-5 downstream of JAM-A, to thus enhance vascular barrier function. Accordingly, gain-of-function for C/EBP-α increased claudin-5 expression and decreased endothelial permeability, as measured by the passage of fluorescein isothiocyanate (FITC)-dextran through endothelial monolayers. Conversely, C/EBP-α loss-of-function showed the opposite effects of decreased claudin-5 levels and increased endothelial permeability. Mechanistically, JAM-A promoted C/EBP-α expression through suppression of β-catenin transcriptional activity, and also through activation of EPAC (exchange protein directly activated by cAMP). C/EBP-α then directly binds the promoter of claudin-5 to thereby promote its transcription. Finally, JAM-A-C/EBP-α-mediated regulation of claudin-5 was lost in blood vessels from tissue biopsies from patients with glioblastoma and ovarian cancer.

Conclusions: We describe here a novel role for the transcription factor C/EBP-α that is positively modulated by JAM-A, a component of tight junctions that acts through EPAC to up-regulate the expression of claudin-5, to thus decrease endothelial permeability. Overall, these data unravel a regulatory molecular pathway through which tight junctions limit vascular permeability. This will help in the identification of further therapeutic targets for diseases associated with endothelial barrier dysfunction. Graphic Abstract: An graphic abstract is available for this article.

Keywords: claudin-5; endothelium; junctional adhesion molecule A; tight junctions; vascular permeability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Capillary Permeability*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Claudin-5 / genetics
  • Claudin-5 / metabolism*
  • Endothelial Cells / metabolism*
  • Female
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Neovascularization, Pathologic
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Tight Junctions / genetics
  • Tight Junctions / metabolism*
  • Up-Regulation


  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • CEBPA protein, mouse
  • CLDN5 protein, human
  • Cell Adhesion Molecules
  • Claudin-5
  • Cldn5 protein, mouse
  • F11R protein, human
  • F11r protein, mouse
  • Receptors, Cell Surface