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

作者：Nikolaos Kakogiannos, Laura Ferrari, Costanza Giampietro, Anna Agata Scalise, Claudio Maderna, Micol Ravà, Andrea Taddei, Maria Grazia Lampugnani, Federica Pisati, Matteo Malinverno, Emanuele Martini, Ilaria Costa, Michela Lupia, Ugo Cavallaro, Galina V. Beznoussenko, Alexander A. Mirоnоv, Bethania Fernandes, Noemi Rudini, Elisabetta Dejana, Monica Giannotta · 发表于：Circulation Research · 年份：2020 · DOI：10.1161/circresaha.120.316742 · 被引用次数：130 · 研究领域：Barrier Structure and Function Studies、Cell Adhesion Molecules Research、Angiogenesis and VEGF in Cancer

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...