Critical Role of the Endothelial αV/β5 Integrin Receptor Signaling Pathway in Promoting Irisin-induced Hippocampal BDNF Expression

Irisin, a myokine released into the bloodstream during physical exercise, is recognized for its role in modulating hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the exact mechanisms by which irisin elevates BDNF levels are not fully understood. Notably, the αV/β5 integrin receptor, identified as a critical receptor for irisin primarily observed in bone and adipose tissues, was shown to play a key role in endothelial cells. Considering that irisin has nitric oxide (NO)-dependent vasodilatory effects and that NO increases endothelial BDNF production, with approximately 50% of cerebral BDNF expression derived from cerebral endothelium, we aimed to explore the molecular mechanisms through which irisin regulates BDNF levels in the hippocampus with a focus on the endothelium. Our findings indicated that recombinant irisin (r-irisin) treatment of hippocampal slices led to an increase in BDNF expression and that this effect was blocked by cilengitide, an αV/β5 integrin antagonist. Mechanistically, r-irisin activated focal adhesion kinase (FAK), and this activation was also inhibited by cilengitide. In vivo, we observed that exercised rats exhibited enhanced FAK activation with a positive correlation between FAK phosphorylation and serum irisin levels as well as FAK phosphorylation and hippocampal BDNF expression. Additionally, αV/β5 integrins, phosphorylated endothelial NO synthase (p-eNOS), and BDNF were significantly elevated in the hippocampal endothelial cells of exercised rats. These findings reveal that irisin may upregulate BDNF expression in the hippocampal through a mechanism dependent on endothelial αV/β5 integrins and the FAK/eNOS signaling pathway, supporting its potential as a therapeutic target for enhancing NO-dependent BDNF expression.