Endothelial Cell- Astrocyte Interactions

Recent advances in cell biology open the way for studying aspects of blood-brain bamer (BBB) formation and function that have puzzled investigators since Ehrlich and Goldmann first described the barrier. Although the endothelial cells in the microvessels of all tissues appear to arise from common mesodermal precursors, considerable organ-to-organ variability exists in their ultrastructure and permeability. The most extreme example of restricted microvascular permeability is found in brain, where the endothelial cells are sealed together by continuous complex tight junctions to form a polarized “epithelium” that regulates the passage of small organic molecules and ions between blood and brain.‘ A constant feature of brain microvessels with barrier properties is an almost total investment with processes from astrocytes.2 This contact is so extensive that the astrocytes were once thought to physically create the BBB. We now know from the classic tracer studies of Reese, Karnovsky, and Brightman that the anatomic basis of the BBB is provided by the unfenestrated endothelial cells with their continuous and complex tight j~nctions.~ Although astrocytic processes encircle the capillaries and attach to a basement membrane shared with the endothelial cells, the foot processes are not sealed to each other and small gaps between the astrocytes allow passage of proteins and other polar molecules in the interstitial fluid up to the abluminal surface of the endothelial cells (FIG. 1). Even though the astrocytes do not create a physical barrier, their close contact with brain microvessels suggests that they have an important role in the function of the BBB.‘ Evidence for a direct influence of brain cells upon microvascular function is provided by the elegant chimeric experiments of Stewart and Wiley? These investigators implanted embryonic avascular quail brain into the abdominal cavity of a chick embryo. Because of the marked difference in nuclear structure between the quail and the chicken, Stewart and Wily could prove that the blood vessels that formed in the transplanted brain arose from the abdominal vasculature of the chicken (FIG. 2). Despite their systemic origin, the chick microvessels growing into the quail brain exhibited the restricted permeability, special structure, and enzymes characteristic of the BBB. In contrast, microvessels growing into embryonic quail muscle implanted into chick brain were highly permeable and lacked BBB enzymes even though they were derived from chick brain. These studies demonstrate a direct influence of brain upon endothelial cell differentiation.