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 strictly 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 endothelium a tight barrier for water soluble moleucles. In combination with its expression of specific enzymes and transport molecules, the BBB endothelium is unique and distinguishable from all other endothelial cells in the body. During embryonic development, the CNS is vascularized by angiogenic 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 mechanisms mediating 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 associated with many human diseases such as multiple sclerosis, stroke and brain tumors, we discuss recent insights into the molecular mechanisms involved in maintaining barrier characteristics in the mature BBB endothelium.
Highlights
The developing vertebrate central nervous system (CNS) derives from the ectoderm germ cell layer, a tissue that is devoid of vascular progenitor cells and that lacks the capacity to generate endothelial cells
Growth of the CNS depends on the delivery of oxygen and nutrients from blood vessels that invade the brain from the surrounding mesoderm
Classic studies on embryonic CNS vascularization of the chick, rat and rabbit cerebral cortex by using a combination of India ink perfusion and light and transmission electron microscopy have revealed that blood vessels first form a perineural vascular plexus (PNVP) and invade the neural tube and branch in a precise spatio-temporal manner (Bär 1983; Freeney and Watterson 1946; Strong 1964)
Summary
The developing vertebrate central nervous system (CNS) derives from the ectoderm germ cell layer, a tissue that is devoid of vascular progenitor cells and that lacks the capacity to generate endothelial cells. The embryonic brain tissue grafts were vascularized by sprouting angiogenesis from the nonbrain host and developed BBB characteristics including the expression of BBB-specific molecules (Ikeda et al 1996), providing experimental evidence that endothelial cells from invading host vessels differentiate into BBB-forming vessels under the influence of the premature neuroectoderm. Barrier induction most likely takes place well before astrocytes differentiate; neuroblasts are speculated to contribute to BBB differentiation (summarized in Bauer and Bauer 2000) This barrier-inductive capacity of neuroblasts has been confirmed more recently in experiments that implicate neuroblast-derived Wnt growth factors in this process (Lippmann et al 2012; Weidenfeller et al 2007). In apparent contrast to these observations, vascular sprouts have been observed to be tight for serum proteins from the earliest stages of invasion into the developing CNS (summarized in Saunders et al 2012)
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