Gliovascular interface abnormality in mice with endothelial cell senescence
Gliovascular interface abnormality in mice with endothelial cell senescence
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DOI：
10.1002/glia.24287
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发表时间：
2022-10-26
期刊：
影响因子：
6.2
通讯作者：
Rikitake, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Kawauchi, Shoji;Mizoguchi, Taiji;Rikitake, Yoshiyuki
在脑中，神经元、神经胶质细胞、血管内皮细胞（EC）和壁细胞形成被称为神经血管单元（NVU）的功能结构。NVU的功能随着年龄的增长而受损。为了深入了解NVU中与衰老相关的变化的机制，我们在本研究中表征了转基因小鼠的胶质血管界面，该转基因小鼠使用Tie 2启动子在EC中特异性表达显性阴性形式的端粒重复序列结合因子2（TERF 2）。在这些转基因小鼠中，衰老发生在脑EC中，并伴随着促炎细胞粘附分子和细胞因子的mRNA的上调。值得注意的是，在大脑皮层的深层中，星形胶质细胞表现出S100 β信号的增加以及水通道水通道蛋白-4（AQP 4）向星形胶质细胞血管周围端足的极化的减少。机械地，肌营养不良蛋白聚糖及其配体层粘连蛋白α 2的血管周围定位降低，并且它们的定位与AQP 4的血管周围定位良好相关，这支持它们的相互作用调节AQP 4的血管周围定位的概念。层粘连蛋白α 2的血管周围定位的减少可能归因于其由衰老的EC释放的基质金属蛋白酶-2的蛋白水解降解。周细胞覆盖率增加，并与AQP 4血管周围定位的减少呈负相关。我们建议，内皮细胞的衰老相关的变化诱导了星形胶质细胞的轻微形态学改变，并影响AQP 4在胶质血管界面的定位。
In the brain, neurons, glial cells, vascular endothelial cells (ECs), and mural cells form a functional structure referred to as the neurovascular unit (NVU). The functions of the NVU become impaired with aging. To gain insight into the mechanism underlying the aging-related changes in the NVU, we characterized in the present study the gliovascular interface in transgenic mice expressing a dominant-negative form of the telomeric repeat-binding factor 2 (TERF2) specifically in ECs using the Tie2 promoter. In these transgenic mice, senescence occurred in the cerebral ECs and was accompanied by upregulation of the mRNAs of proinflammatory cell adhesion molecules and cytokines. It is noteworthy that in the deep layers of the cerebral cortex, astrocytes exhibited an increase in the signals for S100 beta as well as a decrease in the polarization of the water channel aquaporin-4 (AQP4) to the perivascular endfeet of the astrocytes. Mechanistically, the perivascular localization of dystroglycan and its ligand, laminin alpha 2, was decreased, and their localization correlated well with the perivascular localization of AQP4, which supports the notion that their interaction regulates the perivascular localization of AQP4. The diminished perivascular localization of laminin alpha 2 may be attributed to its proteolytic degradation by the matrix metalloproteinase-2 released by senescent ECs. Pericyte coverage was increased and negatively correlated with the decrease in the perivascular localization of AQP4. We propose that aging-related changes in ECs induce a mild morphological alteration of astrocytes and affect the localization of AQP4 at the gliovascular interface.