Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614. United States.
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614. United States.
CNS Neurol Disord Drug Targets. 2017;16(3):279-290. doi: 10.2174/1871527316666170117115040.
The blood brain barrier (BBB) is a continuous, non-fenestrated vessel system that tightly regulates the movement of molecules, ions, and cells between the blood and the central nervous system. Endothelial cells are the major constituents of the BBB and these cells are linked to each other through intercellular contact points composed of tight junctions, adherent junctions and gap junctions. These three types of junctions are connected to the intracellular actin cytoskeleton via various adaptor proteins. Thus, the actin cytoskeleton plays a crucial role in regulating the stability of endothelial cell contacts and vascular permeability. Shear stress, growth factors, and Wnt/β-catenin pathway modulators contribute to maintaining endothelial cell integrity by controlling actin dynamics under homeostatic conditions. Interestingly, the downstream signaling of the aforementioned factors converges at Rac1, which mediates cortical actin stabilization, stress fiber destabilization and junctional complex stabilization by controlling subcellular cofilin dynamics. However, Rac1 is not the only modulator of cofilin activity; many other agents activated during inflammatory, ischemic, and excitotoxic conditions can disturb homeostatic cofilin dynamics and induce BBB disruption. Therefore, in this review, we discuss organization of the actin cytoskeleton in BBB endothelial cells and how interactions between the actin cytoskeleton and junctional complexes are maintained during homeostatic conditions. Furthermore, we discuss how an imbalance in subcellular cofilin dynamics can contribute to BBB disruption and highlight Rac1 as a potential target that can be exploited to preserve BBB stability.
血脑屏障（BBB）是一个连续的、无窗孔的血管系统，它严格调节血液和中枢神经系统之间分子、离子和细胞的运动。内皮细胞是 BBB 的主要组成部分，这些细胞通过由紧密连接、黏附连接和缝隙连接组成的细胞间接触点彼此相连。这三种类型的连接通过各种衔接蛋白与细胞内的肌动蛋白细胞骨架相连。因此，肌动蛋白细胞骨架在调节内皮细胞连接的稳定性和血管通透性方面起着至关重要的作用。切应力、生长因子和 Wnt/β-连环蛋白途径调节剂通过控制肌动蛋白动力学在稳态条件下有助于维持内皮细胞的完整性。有趣的是，上述因素的下游信号通路汇集到 Rac1，它通过控制亚细胞 cofilin 动力学来介导皮质肌动蛋白的稳定、应力纤维的解稳定和连接复合体的稳定。然而，Rac1 不是 cofilin 活性的唯一调节剂；在炎症、缺血和兴奋毒性等情况下激活的许多其他因子可以扰乱稳态 cofilin 动力学并导致 BBB 破坏。因此，在这篇综述中，我们讨论了 BBB 内皮细胞中肌动蛋白细胞骨架的组织，以及在稳态条件下肌动蛋白细胞骨架与连接复合体之间的相互作用是如何维持的。此外，我们还讨论了亚细胞 cofilin 动力学的不平衡如何导致 BBB 破坏，并强调 Rac1 作为一个潜在的靶点，可以被利用来维持 BBB 的稳定性。
