Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces
Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces
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DOI：
10.1016/j.devcel.2018.10.017
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发表时间：
2018-12-17
影响因子：
11.8
通讯作者：
Levkowitz, Gil
中科院分区：
文献类型：
--
作者：
Anbalagan, Savani;Gordon, Ludmila;Levkowitz, Gil
下丘脑-神经垂体系统(HNS)通过缺乏血脑屏障(BBB)的通透性毛细血管传递神经激素和血载蛋白来调节动态平衡。为什么神经垂体毛细血管变得可渗透，而邻近的脑血管形成血脑屏障，目前尚不清楚。我们发现，神经垂体部的常驻星形胶质细胞--垂体细胞--表达与神经炎症期间血脑屏障破坏相关的基因。富含垂体细胞的因子提供了一个局部微环境，引导一个可渗透的神经血管管道。因此，VEGFA和转化生长因子β3的遗传和药理扰动影响了HNS血管的形态发生和通透性，并损害了窗口标记plvap的表达。抗炎剂地塞米松降低了HNS的通透性，并下调了脑垂体细胞特异的cyp26b基因，该基因编码一种维甲酸分解代谢酶。抑制Cyp26b活性导致紧密连接蛋白Claudin-5表达上调，通透性降低。我们的结论是，脑垂体细胞衍生因子调节内皮细胞的“决定”，采用可渗透的内皮细胞命运，而不是形成血脑屏障。
The hypothalamo-neurohypophyseal system (HNS) regulates homeostasis through the passage of neurohormones and blood-borne proteins via permeable blood capillaries that lack the blood-brain barrier (BBB). Why neurohypophyseal capillaries become permeable while the neighboring vasculature of the brain forms BBB remains unclear. We show that pituicytes, the resident astroglial cells of the neurohypophysis, express genes that are associated with BBB breakdown during neuroinflammation. Pituicyte-enriched factors provide a local microenvironment that instructs a permeable neurovascular conduit. Thus, genetic and pharmacological perturbations of Vegfa and Tgf beta 3 affected HNS vascular morphogenesis and permeability and impaired the expression of the fenestral marker plvap. The anti-inflammatory agent dexamethasone decreased HNS permeability and downregulated the pituicyte-specific cyp26b gene, encoding a retinoic acid catabolic enzyme. Inhibition of Cyp26b activity led to upregulation of tight junction protein Claudin-5 and decreased permeability. We conclude that pituicyte-derived factors regulate the "decision" of endothelial cells to adopt a permeable endothelial fate instead of forming a BBB.