Research Paper|Volume 12, Issue 12|pp 11781—11793

Astrocyte-derived VEGF increases cerebral microvascular permeability under high salt conditions

Zhezhi Deng^1,², Li Zhou², Yuge Wang², Siyuan Liao², Yinong Huang², Yilong Shan², Sha Tan², Qin Zeng², Lisheng Peng², Haiwei Huang¹, Zhengqi Lu²

¹Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China
²Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China

Received: December 30, 2019Accepted: April 17, 2020Published: June 22, 2020

https://doi.org/10.18632/aging.103348

Copyright © 2020 Deng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.