Abstract
Blood-central nervous system (CNS) barriers are physiological interfaces separating the neural tissue from circulating blood and are essential for neuronal function and cellular homeostasis. Endothelial cells that form the walls of CNS blood vessels constitute these barriers but barrier properties are not intrinsic to these cells; rather they are actively induced and maintained by the surrounding CNS microenvironment. Notably, the abluminal surface of CNS capillary endothelial cells is ensheathed by pericytes and astrocytic endfeet. However, the specific extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted specifically by CNS pericytes as an essential factor in regulating blood-CNS barrier function via interactions with its integrin receptor in adjacent endothelial cells. Genetic ablation of vitronectin results in leaky blood-CNS barriers, despite having normal pericyte coverage and vascular patterning. Electron microscopy reveals increased transcytosis in endothelial cells of Vtn−/− mice without functional defects in tight-junctions. We further demonstrate that vitronectin binding to integrin receptors is essential for barrier function, as mice harboring a point mutation in vitronectin that specifically abolishes integrin binding, VtnRGE, phenocopy the barrier defects in Vtn−/− mice. Furthermore, endothelial-specific deletion of integrin α5, an RGD-ligand binding integrin receptor that is expressed in CNS endothelial cells, also results in similar blood-CNS barrier defects as observed in Vtn−/− and VtnRGE mice. Finally, integrin α5 activation by vitronectin inhibits transcytosis in endothelial cells and vitronectin-integrin α5 signaling regulates barrier function independent of the caveolae pathway. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.
Summary Vitronectin-integrin signaling between pericytes and CNS endothelial cells regulates blood-CNS barrier function
Competing Interest Statement
The authors have declared no competing interest.