Institute of Anatomy and Cell Biology, Julius-Maximilians-Universität Würzburg, Koellikerstrasse 6, Würzburg, Germany.
Cardiovasc Res. 2010 Jul 15;87(2):243-53. doi: 10.1093/cvr/cvq086. Epub 2010 Mar 17.
Inflammatory mediators increase vascular permeability primarily by formation of intercellular gaps between endothelial cells of post-capillary venules. Under these conditions, endothelial cell-cell contacts such as adherens and tight junctions open to allow paracellular fluid passage. Small guanosine triphosphatases (GTPases) from the ras superfamily, primarily Rho GTPases (RhoA, Rac1, Cdc42) or Rap1 are known to regulate cell adhesion, in part by reorganization of the junction-associated cortical actin cytoskeleton. In this review, we will discuss the role of small GTPases for the maintenance of microvascular barrier functions under resting conditions as well as under conditions of increased permeability and their involvement in signalling pathways downstream of both barrier-stabilizing and inflammatory mediators. Rac1 and Cdc42 are the main GTPases required for barrier maintenance and stabilization, whereas RhoA negatively regulates barrier properties under both resting and inflammatory conditions. For Rac1 and RhoA, contrary functions under certain conditions have also been described. However, Rac1-mediated barrier destabilization in microvascular endothelium appears to be largely restricted to conditions of enhanced endothelial cell migration and thus to be more closely related to angiogenesis rather than to inflammation. Recent studies revealed that cAMP signalling, which is well known to be barrier protective, enhances barrier functions in part via Rap1-mediated activation of Rac1 and Cdc42 as well as by inhibition of RhoA. Moreover, barrier-stabilizing mediators directly activate Rac1 and Cdc42 or increase cAMP levels. On the other hand, several barrier-disruptive components appear to increase permeability by reduced formation of cAMP, leading to both inactivation of Rac1 and activation of RhoA.
炎症介质主要通过后毛细血管微静脉内皮细胞之间的细胞间隙形成来增加血管通透性。在这些条件下，内皮细胞-细胞连接处的粘附连接和紧密连接打开，允许细胞旁液通过。小 G 蛋白（GTPases）中的 ras 超家族，主要是 Rho GTPases（RhoA、Rac1、Cdc42）或 Rap1，已知可以调节细胞粘附，部分通过连接相关皮质肌动球蛋白细胞骨架的重排。在这篇综述中，我们将讨论小 GTPases 在维持微血管屏障功能方面的作用，包括在休息条件下以及通透性增加条件下的作用，以及它们在屏障稳定和炎症介质下游信号通路中的作用。Rac1 和 Cdc42 是维持和稳定屏障所必需的主要 GTPases，而 RhoA 在休息和炎症条件下均负调节屏障特性。对于 Rac1 和 RhoA，在某些条件下也描述了相反的功能。然而，Rac1 介导的微血管内皮屏障失稳似乎主要限于增强内皮细胞迁移的条件，因此与血管生成而不是炎症更为密切相关。最近的研究表明，cAMP 信号通路，众所周知具有屏障保护作用，部分通过 Rap1 介导的 Rac1 和 Cdc42 的激活以及 RhoA 的抑制来增强屏障功能。此外，屏障稳定介质直接激活 Rac1 和 Cdc42 或增加 cAMP 水平。另一方面，几种破坏屏障的成分似乎通过减少 cAMP 的形成来增加通透性，从而导致 Rac1 的失活和 RhoA 的激活。
