1. JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function.
- Author
-
Kakogiannos N, Ferrari L, Giampietro C, Scalise AA, Maderna C, Ravà M, Taddei A, Lampugnani MG, Pisati F, Malinverno M, Martini E, Costa I, Lupia M, Cavallaro U, Beznoussenko GV, Mironov AA, Fernandes B, Rudini N, Dejana E, and Giannotta M
- Subjects
- Adult, Aged, Animals, Brain Neoplasms metabolism, Brain Neoplasms pathology, CCAAT-Enhancer-Binding Proteins genetics, Cell Adhesion Molecules genetics, Cell Line, Claudin-5 genetics, 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, Signal Transduction, Tight Junctions genetics, Up-Regulation, CCAAT-Enhancer-Binding Proteins metabolism, Capillary Permeability, Cell Adhesion Molecules metabolism, Claudin-5 metabolism, Endothelial Cells metabolism, Receptors, Cell Surface metabolism, Tight Junctions metabolism
- Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF