ABSTRACT
The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery. An unbiased lipidomic analysis reveals significant differences in endothelial cell lipid signatures from the CNS and periphery, which underlie a suppression of caveolae vesicle formation and trafficking in brain endothelial cells. Furthermore, lipids transported by Mfsd2a establish a unique lipid environment that inhibits caveolae vesicle formation in CNS endothelial cells to suppress transcytosis and ensure BBB integrity.
Subject(s)
Blood-Brain Barrier/metabolism , Caveolae/metabolism , Lipid Metabolism/genetics , Membrane Transport Proteins/genetics , Transcytosis/genetics , Animals , Blood-Brain Barrier/ultrastructure , Blotting, Western , Caveolae/ultrastructure , Endothelial Cells , HEK293 Cells , Humans , Immunohistochemistry , Membrane Transport Proteins/metabolism , Mice , Mice, Knockout , Microscopy, Confocal , Microscopy, Electron, Transmission , Permeability , SymportersABSTRACT
Blood-central nervous system (CNS) barriers partition neural tissues from the blood, providing a homeostatic environment for proper neural function. The endothelial cells that form blood-CNS barriers have specialized tight junctions and low rates of transcytosis to limit the flux of substances between blood and CNS. However, the relative contributions of these properties to CNS barrier permeability are unknown. Here, by studying functional blood-retinal barrier (BRB) formation in mice, we found that immature vessel leakage occurs entirely through transcytosis, as specialized tight junctions are functional as early as vessel entry into the CNS. A functional barrier forms only when transcytosis is gradually suppressed during development. Mutant mice with elevated or reduced levels of transcytosis have delayed or precocious sealing of the BRB, respectively. Therefore, the temporal regulation of transcytosis governs the development of a functional BRB, and suppression of transcytosis is a principal contributor for functional barrier formation.
Subject(s)
Blood-Retinal Barrier/growth & development , Transcytosis/physiology , Animals , Blood-Retinal Barrier/ultrastructure , Caveolin 1/genetics , Caveolin 1/physiology , Endothelial Cells/physiology , Female , Male , Membrane Transport Proteins/biosynthesis , Membrane Transport Proteins/genetics , Membrane Transport Proteins/physiology , Mice , Mice, Knockout , Symporters , Tight Junctions/genetics , Tight Junctions/physiology , Transcytosis/geneticsABSTRACT
The blood-brain barrier (BBB) maintains the optimal microenvironment in the central nervous system (CNS) for proper brain function. The BBB comprises specialized CNS endothelial cells with fundamental molecular properties essential for the function and integrity of the BBB. The restrictive nature of the BBB hinders the delivery of therapeutics for many neurological disorders. In addition, recent evidence shows that BBB dysfunction can precede or hasten the progression of several neurological diseases. Despite the physiological significance of the BBB in health and disease, major discoveries of the molecular regulators of BBB formation and function have occurred only recently. This review highlights recent findings describing the molecular determinants and core cellular pathways that confer BBB properties on CNS endothelial cells.
