REVIEW Novel insights into the development and maintenance of the blood–brain barrier

Abstract The blood–brain barrier (BBB) is essential for maintaining homeostasis within the central nervous system (CNS) and is a prerequisite for proper neuronal function. The BBB is localized to microvascular endothelial cells that strict-ly control the passage of metabolites into and out of the CNS. Complex and continuous tight junctions and lack of fenestrae combined with low pinocytotic activity make the BBB endo-thelium a tight barrier for water soluble moleucles. In combi-nation with its expression of specific enzymes and transport molecules, the BBB endothelium is unique and distinguish-able from all other endothelial cells in the body. During embryonic development, the CNS is vascularized by angio-genic sprouting from vascular networks originating outside of the CNS in a precise spatio-temporal manner. The particular barrier characteristics of BBB endothelial cells are induced during CNS angiogenesis by cross-talk with cellular and acellular elements within the developing CNS. In this review, we summarize the currently known cellular and molecular mechanismsmediating brain angiogenesis and introduce more recently discovered CNS-specific pathways (Wnt/β−catenin, Norrin/Frizzled4 and hedgehog) and molecules (GPR124) that are crucial in BBB differentiation and maturation. Finally, based on observations that BBB dysfunction is asso-ciated with many human diseases such as multiple sclerosis, stroke and brain tumors, we discuss recent insights into the molecular mechanisms involved in maintaining barrier char-acteristics in the mature BBB endothelium. Keywords Blood-brain barrier (BBB). Tight junctions