Targeting Epac1 to protect the blood brain barrier from inflammation-induced dysfunction: Evidence from an in vitro model
Aims Exchange protein directly activated by cyclic AMP 1 (Epac1), a direct effector of cyclic AMP (cAMP), has been implicated in the regulation of endothelial permeability in peripheral tissues. However, its potential role in protecting the blood-brain barrier (BBB) under inflammatory conditions has...
| Autores: | , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Santiago de Compostela (USC) |
| Repositorio: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela |
| Idioma: | inglés |
| OAI Identifier: | oai:dnet:minerva_____::f68dbd85a8976a63d3b9898939d9d4a6 |
| Acceso en línea: | https://hdl.handle.net/10347/47418 |
| Access Level: | acceso abierto |
| Palabra clave: | Inflammation Blood brain barrier Transendothelial electrical resistence cAMP pathway Epac1 Neurodegenerative diseases |
| Sumario: | Aims Exchange protein directly activated by cyclic AMP 1 (Epac1), a direct effector of cyclic AMP (cAMP), has been implicated in the regulation of endothelial permeability in peripheral tissues. However, its potential role in protecting the blood-brain barrier (BBB) under inflammatory conditions has not been previously explored. In this study, we evaluated for the first time the impact of selective Epac1 activation on BBB integrity using an in vitro model of brain microvascular endothelial cells (bEnd.3) exposed to lipopolysaccharide (LPS). Materials and methods Cells were cultured in Transwell systems and treated with selective activators or inhibitors of Epac1 and protein kinase A (PKA). Barrier function was assessed through transendothelial electrical resistance (TEER), tight junction protein expression and localization, reactive oxygen species (ROS) production, pro-inflammatory gene expression, and macrophage adhesion assays. Key findings Our results show that Epac1 activation significantly prevented the LPS-induced decrease in TEER values, preserved claudin-5 expression, reduced oxidative stress, and stabilized cytoskeletal organization. PKA activation alone did not restore TEER or protect barrier integrity. However, both Epac1 and PKA were required to reduce macrophage adhesion and vascular cell adhesion molecule 1 (VCAM-1) expression, suggesting complementary roles in modulating inflammatory activation. Significance These findings identify Epac1 as a novel modulator of BBB integrity during inflammation and support the therapeutic potential of selectively targeting cAMP signaling pathways to preserve BBB function in neurodegenerative diseases associated with neuroinflammation. |
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