In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the alpha 6 beta 4 integrin and dystroglycan.
In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the alpha 6 beta 4 integrin and dystroglycan.
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DOI：
10.1002/glia.20995
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发表时间：
2010-08
期刊：
影响因子：
6.2
通讯作者：
Milner, Richard
中科院分区：
文献类型：
--
作者：
Li, Longxuan;Welser, Jennifer V.;Dore-Duffy, Paula;Del Zoppo, Gregory J.;Lamanna, Joseph C.;Milner, Richard
脑缺氧诱导中枢神经系统（CNS）产生深刻的血管生成反应。利用小鼠慢性脑缺氧模型，我们先前证明了缺氧CNS血管生成血管中细胞外基质（ECM）蛋白纤维连接蛋白的显著上调，以及其主要受体α5β1整合素在脑内皮细胞（BEC）上的表达增加。由于脑缺氧也会导致神经胶质细胞激活，因此本研究的目的是确定脑缺氧模型中BEC反应与神经胶质细胞激活之间的时间关系。结果表明，缺氧4 d后，BEC纤维连接蛋白/α5β1整合素的表达和增殖均达到最大水平。有趣的是，缺氧4天，所有分裂细胞都是BEC，但在稍后的时间点也观察到增生的星形胶质细胞。GFAP染色显示，缺氧诱导星形胶质细胞明显活化，在缺氧7 ~ 14 d达到最大水平。由于新形成的脑毛细血管需要星形胶质细胞端足的包裹才能获得成熟的脑内皮特征，我们接下来研究了缺氧如何调节星形胶质细胞端足粘附分子的表达。这表明星形胶质细胞粘附受体α6β4整联素和异常糖聚糖均显著上调，其时间过程与星形胶质细胞活化非常相似。综上所述，这一证据表明脑缺氧首先促进内皮反应，其中纤维连接蛋白促进BEC增殖。随后是星形胶质细胞反应，包括星形胶质细胞的激活、增殖和星形胶质细胞端足的重组，这与星形胶质细胞端足粘附分子的表达增加有关。
Cerebral hypoxia induces a profound angiogenic response in the central nervous system (CNS). Using a mouse model of chronic cerebral hypoxia, we previously demonstrated that angiogenic vessels in the hypoxic CNS show marked upregulation of the extracellular matrix (ECM) protein fibronectin, along with increased expression of its major receptor, α5β1integrin on brain endothelial cells (BEC). As cerebral hypoxia also leads to glial activation, the aim of the current study was to define the temporal relationship between BEC responses and glial cell activation in this model of cerebral hypoxia. This revealed that BEC fibronectin/α5β1 integrin expression and proliferation both reached maximal level after 4 days hypoxia. Interestingly, up to 4 days hypoxia, all dividing cells were BEC, but at later time-points proliferating astrocytes were also observed. GFAP staining revealed that hypoxia induced marked astrocyte activation that reached maximal level between 7–14 days hypoxia. As newly formed cerebral capillaries require ensheathment by astrocyte end-feet in order to acquire mature brain endothelium characteristics, we next examined how expression of astrocyte end-feet adhesion molecules is regulated by hypoxia. This showed that the astrocyte adhesion receptors α6β4 integrin and dystroglycan were both markedly upregulated, with a time-course that closely resembled astrocyte activation. Taken together, this evidence shows that cerebral hypoxia promotes first an endothelial response, in which fibronectin promotes BEC proliferation. This is then followed by an astrocyte response, involving astrocyte activation, proliferation and re-organization of astrocyte end-feet, which correlates with increased expression of astrocyte end-feet adhesion molecules.
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