Furthermore, the VEGF receptors Flt-1 and Flk-1 exert antagonistic functions in MDD: Flt-1 disrupts BBB tight junctions (e.g., ZO-1, occludin) via the PLCγ/NO pathway, mediating pathological permeability; in contrast, Flk-1 promotes neuronal survival and synaptic plasticity through the PI3K/Akt pathway (Mesquita-Britto et al., 2020; Wang et al., 2024). This evidence concerns the gene AKT1 and major depressive disorder.