Developmental regulation of barrier- and non-barrier blood vessels in the CNS
Developmental regulation of barrier- and non-barrier blood vessels in the CNS
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DOI：
10.1111/joim.13263
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发表时间：
2021-03-04
影响因子：
11.1
通讯作者：
Liebner, S.
中科院分区：
文献类型：
--
作者：
Ben-Zvi, A.;Liebner, S.
血脑屏障（BBB）在中枢神经系统（CNS）中对于创造和维持组织稳态至关重要，而中枢神经系统是神经元正常功能的关键。在大多数脊椎动物中，血脑屏障定位于在神经外胚层血管生成过程中获得屏障特性的微血管内皮细胞。复杂和连续的紧密连接，缺乏窗窗，再加上较低的胞饮活性，使得血脑屏障内皮成为只能通过特定转运体进入中枢神经系统的水溶性分子的紧密屏障。在胚胎发育过程中，这些独特内皮特性的分化是由内皮特异性的Wnt/ β -连环蛋白通路以精确的时空方式启动的。在这篇综述中，我们总结了目前已知的细胞（神经前体细胞和内皮细胞）和分子（VEGF和Wnt/ β -连环蛋白）介导脑血管生成和屏障形成的机制。此外，我们还介绍了最近发现的与发育中的中枢神经系统中细胞和非细胞元件（如细胞外基质）之间的串扰。我们讨论了Wnt/ β -catenin下游分子机制的最新见解，特别是最近发现的靶基因，如Foxf2、Foxl2、Foxq1、Lef1、Ppard、Zfp551、Zic3、Sox17、Apcdd1和Fgfbp1，它们参与完善和维持成熟血脑屏障内皮的屏障特性。此外，我们还介绍了最近对中枢神经系统内屏障异质性和内皮屏障特性差异的研究，重点关注心室周围器官以及心室下区和海马体的神经源性壁龛。最后，强调了在了解血脑屏障发展的背景下，在病理条件下调节血脑屏障功能的策略中获益的开放性问题和未来的血脑屏障研究方向。
The blood-brain barrier (BBB) is essential for creating and maintaining tissue homeostasis in the central nervous system (CNS), which is key for proper neuronal function. In most vertebrates, the BBB is localized to microvascular endothelial cells that acquire barrier properties during angiogenesis of the neuroectoderm. Complex and continuous tight junctions, and the lack of fenestrae combined with low pinocytotic activity render the BBB endothelium a tight barrier for water-soluble molecules that may only enter the CNS via specific transporters. The differentiation of these unique endothelial properties during embryonic development is initiated by endothelial-specific flavours of the Wnt/beta-catenin pathway in a precise spatiotemporal manner. In this review, we summarize the currently known cellular (neural precursor and endothelial cells) and molecular (VEGF and Wnt/beta-catenin) mechanisms mediating brain angiogenesis and barrier formation. Moreover, we introduce more recently discovered crosstalk with cellular and acellular elements within the developing CNS such as the extracellular matrix. We discuss recent insights into the downstream molecular mechanisms of Wnt/beta-catenin in particular, the recently identified target genes like Foxf2, Foxl2, Foxq1, Lef1, Ppard, Zfp551, Zic3, Sox17, Apcdd1 and Fgfbp1 that are involved in refining and maintaining barrier characteristics in the mature BBB endothelium. Additionally, we elute to recent insight into barrier heterogeneity and differential endothelial barrier properties within the CNS, focussing on the circumventricular organs as well as on the neurogenic niches in the subventricular zone and the hippocampus. Finally, open questions and future BBB research directions are highlighted in the context of taking benefit from understanding BBB development for strategies to modulate BBB function under pathological conditions.