Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot 7610001, Israel.
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Dev Cell. 2018 Dec 17;47(6):711-726.e5. doi: 10.1016/j.devcel.2018.10.017. Epub 2018 Nov 15.
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 Tgfβ3 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.
下丘脑-神经垂体系统 (HNS) 通过可渗透的毛细血管传递神经激素和血液蛋白来调节体内平衡,而这些毛细血管缺乏血脑屏障 (BBB)。神经垂体毛细血管为何变得可渗透,而大脑的邻近血管却形成 BBB 尚不清楚。我们发现,神经垂体内的固有星形胶质细胞 - 垂体细胞,表达与神经炎症期间 BBB 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,指导可渗透的神经血管管腔形成。因此,Vegfa 和 Tgfβ3 的基因和药理学扰动影响了 HNS 血管形态发生和通透性,并损害了窗孔标记物 plvap 的表达。抗炎药地塞米松降低了 HNS 的通透性,并下调了垂体细胞特异性 Cyp26b 基因,该基因编码一种视黄酸代谢酶。抑制 Cyp26b 活性导致紧密连接蛋白 Claudin-5 的上调和通透性降低。我们得出结论,垂体细胞衍生的因子调节内皮细胞“决定”采用可渗透的内皮命运,而不是形成 BBB。