Astrocyte-derived VEGF increases cerebral microvascular permeability under high salt conditions
Astrocyte-derived VEGF increases cerebral microvascular permeability under high salt conditions
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DOI：
10.18632/aging.103348
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发表时间：
2020-06-30
期刊：
影响因子：
5.2
通讯作者：
Lu, Zhengqi
中科院分区：
文献类型：
--
作者：
Deng, Zhezhi;Zhou, Li;Lu, Zhengqi
过量盐（NaCI）摄入与多种以脑微血管通透性增加为特征的中枢神经系统（CNS）疾病密切相关。然而，高盐饮食（HSD）和紧密连接（TJs）破裂之间的联系尚不清楚。在本研究中，我们发现高盐并不直接影响内皮细胞之间的屏障，但当内皮细胞与星形胶质细胞共培养时，高盐会抑制TJ蛋白的表达。这种作用与血压无关，但依赖于星形胶质细胞通过NF κ B/MMP-9信号通路激活，导致VEGF表达显著增加。反过来，VEGF通过诱导ERK和eNOS的磷酸化和激活来诱导TJs的破坏。相应地，使用特异性单克隆抗体贝伐单抗阻断VEGF可减弱hsd诱导的TJ蛋白破坏。这些结果揭示了通过vegf引发的炎症反应将HSD与大脑微血管通透性增加联系起来的新轴，这可能是防止HSD对中枢神经系统有害影响的潜在靶点。
Excess salt (NaCI) 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 NF kappa B/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.