Astrocytes-Derived VEGF Induces Blood-Brain Barrier Disruption Under High Salt Condition

Abstract

Background: Excess salt (sodium chloride, NaCl) intake is closely related to a variety of central nervous system (CNS) diseases, which show a core feature of the blood-brain barrier (BBB) disruption. However, less study focus on the link between high salt diet (HSD) and the breakdown of BBB, especially the molecular mechanism remains unclearly elucidated. Methods: First we noticed a positive correlation between urinary sodium levels and first onset acute ischemic stroke patients. A rat model of HSD was established to verify the damage effects on BBB and expression of Vascular Endothelial Growth Factor (VEGF). Then we explore the potential molecular mechanism by a co-cultured model of endothelial cells and astrocytes. Finally, we antagonize VEGF to defend our hypothesis. Findings: In the current study, we reported that HSD suppresses the expression of tight junction proteins, leading to BBB impairment. The effect depends on activation of astrocytes via NFIob/MMP-9 signaling pathway, resulting in a marked increase expression of VEGF. VEGF, in turn, induces disruption of tight junction by activating phosphorylation of ERK and eNOS. Inhibition of VEGF by specific monoclonal antibodies, Bevacizumab, attenuated the effect both in vivo and in vitro, respectively. Interpretation: These results reveal a new axis linking dietary habits to BBB disruption through a VEGF-initiated inflammation response, which may be a potent target to counter the deleterious brain effects. Funding: National Natural Science Foundation of China. Declaration of Interest: None. Ethical Approval: This study was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University, and all participants signed informed consent forms.