Figure 3.

Hemodynamic hypothesis: involvement of cerebral blood flow in EX-induced BDNF increase. EX induces an increase in CBF, leading to elevated FSS. This mechanical stimulation triggers the activation of eNOS through its phosphorylation, resulting in the production of NO. The released NO has the potential to diffuse from endothelial cells to neurons, initiating neuronal BDNF expression. Additionally, endothelial NO has been demonstrated to induce BDNF expression in endothelial cells themselves. Endothelium-derived BDNF may directly bind to neuronal TrkB-FL receptors thus activating neuroplastic pathways. The proximity between synapses and capillaries supports this hypothesis. Alternatively, endothelium-derived BDNF could act in an autocrine manner, amplifying the NO response through endothelial TrkB-FL receptors. In parallel, astrocytes, through their nearby end-feet, might internalize either BDNF or pro-BDNF through their TrkB-T1 or p75^NTR receptors, respectively. Subsequently, they could re-secrete BDNF which might be transferred to neighboring neurons. Finally, the elevation of CBF and subsequent NO production could trigger tPA release. tPA has the potential to cross the BBB via LRP-mediated transcytosis. It could then facilitate neuronal NMDA receptor activation or influence the processing of pro-BDNF to BDNF, through the conversion of plasminogen into plasmin. Alternatively, tPA might facilitate endothelial NMDA receptor activation which could potentially contribute to endothelial BDNF expression. Created with BioRender.com.