Excess salt (NaCl) intake is closely related to a variety of central nervous system (CNS) diseases characterized by increased cerebral microvascular permeability. However, the link between a high salt diet (HSD) and the breakdown of tight junctions (TJs) remains unclear. In the present study, we found that high salt does not directly influence the barrier between endothelial cells, but it suppresses expression of TJ proteins when endothelial cells are co-cultured with astrocytes. This effect is independent of blood pressure, but depends on the astrocyte activation via the NFκB/MMP-9 signaling pathway, resulting in a marked increase in VEGF expression. VEGF, in turn, induces disruption of TJs by inducing phosphorylation and activation of ERK and eNOS. Correspondingly, the HSD-induced disruption of TJ proteins is attenuated by blocking VEGF using the specific monoclonal antibody Bevacizumab. These results reveal a new axis linking a HSD to increased cerebral microvascular permeability through a VEGF-initiated inflammatory response, which may be a potential target for preventing the deleterious effects of HSD on the CNS.