Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Department of Chemistry and Stanford Wu-Tsai Neuroscience Institute, Stanford, CA 94305, USA.
Neuron. 2022 May 18;110(10):1641-1655.e6. doi: 10.1016/j.neuron.2022.02.017. Epub 2022 Mar 15.
Endothelial cells of blood vessels of the central nervous system (CNS) constitute blood-CNS barriers. Barrier properties are not intrinsic to these cells; rather they are induced and maintained by CNS microenvironment. Notably, the abluminal surfaces of CNS capillaries are ensheathed by pericytes and astrocytes. However, extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted by CNS pericytes, as a regulator of blood-CNS barrier function via interactions with its integrin receptor, α5, in endothelial cells. Genetic ablation of vitronectin or mutating vitronectin to prevent integrin binding, as well as endothelial-specific deletion of integrin α5, causes barrier leakage in mice. Furthermore, vitronectin-integrin α5 signaling maintains barrier integrity by actively inhibiting transcytosis in endothelial cells. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.
血脑屏障的血管内皮细胞构成了血脑屏障。这些细胞的屏障特性不是固有存在的，而是由中枢神经系统微环境诱导和维持的。值得注意的是，中枢神经系统毛细血管的基底外侧表面被周细胞和星形胶质细胞所包裹。然而，调节血脑屏障完整性的这些血管周细胞的外在因素在很大程度上还不清楚。在这里，我们通过内皮细胞中整合素受体α5的相互作用，将细胞外基质蛋白纤连蛋白鉴定为一种调节血脑屏障功能的物质，纤连蛋白由中枢神经系统周细胞分泌。纤连蛋白或突变纤连蛋白（阻止整合素结合）的基因缺失，以及内皮细胞特异性整合素α5缺失，都会导致小鼠血脑屏障渗漏。此外，纤连蛋白-整合素α5信号通过主动抑制内皮细胞的转胞吞作用来维持屏障的完整性。这些结果表明，通过配体-受体相互作用从血管周细胞到内皮细胞的信号传递是调节屏障通透性的关键机制。
