Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Compr Physiol. 2012 Jan;2(1):449-78. doi: 10.1002/cphy.c100006.
This article examines the role of the endothelial cytoskeleton in the lung's ability to restrict fluid and protein to vascular space at normal vascular pressures and thereby to protect lung alveoli from lethal flooding. The barrier properties of microvascular endothelium are dependent on endothelial cell contact with other vessel-wall lining cells and with the underlying extracellular matrix (ECM). Focal adhesion complexes are essential for attachment of endothelium to ECM. In quiescent endothelial cells, the thick cortical actin rim helps determine cell shape and stabilize endothelial adherens junctions and focal adhesions through protein bridges to actin cytoskeleton. Permeability-increasing agonists signal activation of "small GTPases" of the Rho family to reorganize the actin cytoskeleton, leading to endothelial cell shape change, disassembly of cortical actin rim, and redistribution of actin into cytoplasmic stress fibers. In association with calcium- and Src-regulated myosin light chain kinase (MLCK), stress fibers become actinomyosin-mediated contractile units. Permeability-increasing agonists stimulate calcium entry and induce tyrosine phosphorylation of VE-cadherin (vascular endothelial cadherin) and β-catenins to weaken or pull apart endothelial adherens junctions. Some permeability agonists cause latent activation of the small GTPases, Cdc42 and Rac1, which facilitate endothelial barrier recovery and eliminate interendothelial gaps. Under the influence of Cdc42 and Rac1, filopodia and lamellipodia are generated by rearrangements of actin cytoskeleton. These motile evaginations extend endothelial cell borders across interendothelial gaps, and may initiate reannealing of endothelial junctions. Endogenous barrier protective substances, such as sphingosine-1-phosphate, play an important role in maintaining a restrictive endothelial barrier and counteracting the effects of permeability-increasing agonists.
本文探讨了内皮细胞细胞骨架在肺部限制液体和蛋白质进入血管空间的能力中的作用，在正常血管压力下，肺部肺泡免受致命性积水的影响。微血管内皮的屏障特性取决于内皮细胞与其他血管壁衬里细胞以及基底细胞外基质（ECM）的接触。黏附斑复合物对于内皮细胞与 ECM 的附着至关重要。在静止的内皮细胞中，厚的皮质肌动蛋白环有助于确定细胞形状，并通过与肌动蛋白细胞骨架的蛋白桥稳定内皮细胞黏附连接和黏附斑。增加通透性的激动剂信号激活 Rho 家族的“小 GTPases”，以重排肌动蛋白细胞骨架，导致内皮细胞形状变化、皮质肌动蛋白环的解体以及肌动蛋白重新分布到细胞质应力纤维中。与钙和Src 调节的肌球蛋白轻链激酶（MLCK）相关联，应力纤维成为肌动球蛋白介导的收缩单位。增加通透性的激动剂刺激钙内流并诱导 VE-钙黏蛋白（血管内皮钙黏蛋白）和β-连环蛋白的酪氨酸磷酸化，从而削弱或拉开内皮细胞黏附连接。一些通透性激动剂导致小 GTPases、Cdc42 和 Rac1 的潜在激活，这有助于内皮屏障的恢复并消除内皮细胞之间的间隙。在 Cdc42 和 Rac1 的影响下，肌动蛋白细胞骨架的重排产生了丝状伪足和片状伪足。这些运动性的突起延伸了内皮细胞边界，跨越内皮细胞之间的间隙，并可能启动内皮连接的重新连接。内源性屏障保护物质，如鞘氨醇-1-磷酸，在维持限制内皮屏障和抵消增加通透性激动剂的作用方面发挥着重要作用。
