DIFFERENTIATION OF BLOOD-BRAIN-BARRIER ENDOTHELIAL-CELLS

The vascular system of the central nervous system is derived from capi llary endothelial cells, which have invaded the early embryonic neuroe ctoderm from the perineural vascular plexus. This process is called an giogenesis and is probably regulated by brain-derived factors. Vascula r endothelial cell growth factor (VEGF) is an angiogenic growth factor whose expression correlated with embryonic brain angiogenesis, i.e. e xpression is high in the embryonic brain when angiogenesis occurs and low.in the adult brain when angiogenesis is shut off under normal phys iological conditions. VEGF receptors 1 and 2 (flt-1 and flk-1) as well as the recently identified angiopoietin receptors (tie-1 and tie-2) a re receptor tyrosine kinases specifically expressed in endothelial cel ls. Expression of these receptors is high during brain angiogenesis bu t low in adult blood-brain barrier endothelium. They are required for the proper development of a vascular system, and particularly tie-2 is necessary for brain angiogenesis. Signal transduction by these recept ors regulates endothelial cell growth, permeability and differentiatio n. Blood-brain barrier endothelial cell characteristics (complex tight junctions, low number of vesicles, specialized transport systems) are induced by the local brain environment, e.g. neurons and astrocytes. Tight junctions between brain endothelial cells are the structural bas is for the paracellular impermeability and high electrical resistance of blood-brain barrier endothelium. Association of tight junction part icles with the P-face rather than the number or branching frequency of tight junction strands correlated with blood-brain barrier developmen t and function suggesting that the cytoplasmic anchoring of the tight junctions plays an important role. During inflammation, leukocytes mig rate through blood-brain barrier endothelium. ICAM-1 and VCAM-1 on blo od-brain barrier endothelial cells appear to be the major mediators of these processes while the selectins are absent from brain endothelium in vivo.