College of Pharmacy, University of Minnesota, 1110 Kirby Drive, Duluth, MN, 55812, USA.
Sci Rep. 2016 Nov 3;6:36450. doi: 10.1038/srep36450.
Laminin, a major component of the basement membrane, plays an important role in blood brain barrier regulation. At the neurovascular unit, brain endothelial cells, astrocytes, and pericytes synthesize and deposit different laminin isoforms into the basement membrane. It has been shown that laminin α4 (endothelial laminin) regulates vascular integrity at embryonic/neonatal stage, while astrocytic laminin maintains vascular integrity in adulthood. Here, we investigate the function of pericyte-derived laminin in vascular integrity. Using a conditional knockout mouse line, we report that loss of pericytic laminin leads to hydrocephalus and BBB breakdown in a small percentage (10.7%) of the mutants. Interestingly, BBB disruption always goes hand-in-hand with hydrocephalus in these mutants, and neither symptom is observed in the rest 89.3% of the mutants. Further mechanistic studies show that reduced tight junction proteins, diminished AQP4 expression, and decreased pericyte coverage are responsible for the BBB disruption. Together, these data suggest that pericyte-derived laminin is involved in the maintenance of BBB integrity and regulation of ventricular size/development.
层粘连蛋白是基底膜的主要成分，在血脑屏障的调节中起着重要作用。在神经血管单元中，脑内皮细胞、星形胶质细胞和周细胞合成并将不同的层粘连蛋白异构体沉积到基底膜中。已经表明，层粘连蛋白α4（内皮层粘连蛋白）在胚胎/新生儿期调节血管完整性，而星形胶质细胞层粘连蛋白在成年期维持血管完整性。在这里，我们研究了周细胞衍生的层粘连蛋白在血管完整性中的功能。使用条件性敲除小鼠系，我们报告称，周细胞层粘连蛋白的缺失会导致少数（10.7%）突变体发生脑积水和血脑屏障破裂。有趣的是，在这些突变体中，BBB 破坏总是与脑积水同时发生，而在其余 89.3%的突变体中则没有观察到这两种症状。进一步的机制研究表明，紧密连接蛋白减少、AQP4 表达降低和周细胞覆盖减少是 BBB 破坏的原因。总之，这些数据表明周细胞衍生的层粘连蛋白参与维持血脑屏障的完整性和调节脑室大小/发育。
