Center for Interdisciplinary Research in Biology/Centre National de la Recherche Scientifique, Collège de France, Unité Mixte de Recherche 7241/Institut National de la Santé et de la Recherche Médicale U1050, Paris, France.
J Cereb Blood Flow Metab. 2012 Aug;32(8):1457-67. doi: 10.1038/jcbfm.2012.45. Epub 2012 Apr 4.
Astrocytes, the most prominent glial cell type in the brain, send specialized processes named endfeet, which enwrap blood vessels and express a large molecular repertoire dedicated to the physiology of the vascular system. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction protein connexins 43 and 30 (Cx43 and Cx30) allowing for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. The contribution of astroglial connexins to the physiology of the brain vascular system has never been addressed. Here, we show that Cx43 and Cx30 expression at the level of perivascular endfeet starts from postnatal days 2 and 12 and is fully mature at postnatal days 15 and 20, respectively, indicating that astroglial perivascular connectivity occurs and develops during postnatal blood-brain barrier (BBB) maturation. We demonstrate that mice lacking Cx30 and Cx43 in GFAP (glial fibrillary acidic protein)-positive cells display astrocyte endfeet edema and a partial loss of the astroglial water channel aquaporin-4 and β-dystroglycan, a transmembrane receptor anchoring astrocyte endfeet to the perivascular basal lamina. Furthermore, the absence of astroglial connexins weakens the BBB, which opens upon increased hydrostatic vascular pressure and shear stress. These results demonstrate that astroglial connexins are necessary to maintain BBB integrity.
星形胶质细胞是大脑中最突出的神经胶质细胞类型，它们发出特化的突起，称为终足，包裹着血管，并表达大量专门用于血管系统生理学的分子。星形胶质细胞终足最显著的特征之一是其富含缝隙连接蛋白 connexin 43 和 30（Cx43 和 Cx30），允许离子和小信号分子通过血管周围星形胶质细胞网络进行直接的细胞间运输。星形胶质细胞连接蛋白对脑血管系统生理学的贡献尚未得到解决。在这里，我们表明，血管周围终足水平的 Cx43 和 Cx30 表达始于出生后第 2 天和第 12 天，并且分别在出生后第 15 天和第 20 天完全成熟，这表明星形胶质细胞血管周围连接发生并在出生后血脑屏障（BBB）成熟过程中发展。我们证明，在 GFAP（胶质纤维酸性蛋白）阳性细胞中缺乏 Cx30 和 Cx43 的小鼠表现出星形胶质细胞终足水肿，以及部分丧失星形胶质细胞水通道 aquaporin-4 和β-肌营养不良蛋白，后者是将星形胶质细胞终足锚定在血管周围基膜上的跨膜受体。此外，星形胶质细胞连接蛋白的缺失削弱了 BBB，当血管内静水压力和切应力增加时，BBB 会打开。这些结果表明，星形胶质细胞连接蛋白对于维持 BBB 完整性是必要的。
