Re‐evaluating the role of astrocytes in blood‐brain barrier induction

Abstract

Neural tissue induces brain capillary endothelial cells to express a diverse array of characteristics that allow them to regulate the passage of solutes between the blood and the brain; these features are collectively referred to as the blood-brain barrier (BBB). Because astrocytes are intimately associated with brain capillaries, they have been thought to be the cell type responsible for barrier induction. Widely accepted support of this hypothesis has been derived from experiments showing that astrocytes implanted into the anterior chamber of the rat eye, or onto the chorioallantoic membrane of the chicken embryo, remain unstained by circulating Evan's blue, while grafts of fibroblasts in these sites stain intensely.We have found several limitations associated with placing grafts in either site, leading us to believe that previously reported results are inconclusive. Astrocytes implanted into the anterior chamber form grafts that are poorly vascularized, whereas fibroblast grafts are richly vascularized by vessels which are often fenestrated. This likely accounts for apparent differences in vessel permeability reported by others. We have found that iridial vessels associated with astrocyte grafts do not change their ultrastructure to resemble brain capillaries .Grafting of cells to the chorioallantoic membrane elicits an extensive inflammatory response. Inflammation results in poor delivery of tracers to graft vasculature as well as altering vessel permeability. Treatment of hosts with steroidal anti-inflammatory agents in doses compatible with survival of the host does not resolve the inflammatory response but does allow improved graft survival. Even after treatment with anti-inflammatory agents, however, astrocyte graft vasculature fails to express high levels of a barrier marker, the GLUT-1 isoform of the glucose transporter. Transplantation of avascular embryonic spinal cord, that induces robust vessel ingrowth and GLUT-1 expression in intra-embryonic vessels, was unable to elicit the ingrowth of more than a few vessels from the chorioallantoic membrane vasculature, and none of these expressed glucose transporter. We conclude that the anterior chamber and cho-0 1993 WILEY-LISS, INC rioallantoic membrane are not suitable sites for studying BBB induction, and that there is, at present, no conclusive evidence that mature astrocytes play a significant role in the initial expression of the BBB. o 1993 Wiley-Liss, Inc.

Activation of protein tyrosine kinases and matrix metalloproteinases causes blood‐brain barrier injury: Novel mechanism for neurodegeneration associated with alcohol abuse

“…In particular, in vitro studies of endothelial-astrocytes co-culture model support the idea that astrocytes are essential for the formation of BBB (Holash et al 1993). Direct contact between BMVEC and astrocytes are necessary for optimal tightness of the barrier (Rubin et al 1991), as such, astrocytes end-feet envelop about 99 % of the outer surface of the CNS capillaries (Hawkins and Davis 2005).…”

The Blood-Brain Barrier/Neurovascular Unit in Health and Disease

“…Similarly, culture of brain endothelial cells with astrocytes (Tao-Cheng et al, 1987; Neuhaus et al, 1991) or with astrocyte-conditioned media (Maxwell et al, 1987) has been shown to improve BBB characteristics in vitro. Nonetheless, experiments involving coculture of brain endothelial cells with immature astrocytes have been criticized as inconclusive on methodological grounds, specifically that astrocytes may merely help maintain BBB morphology in culture (Holash et al, 1993). Subsequent in vivo studies have indicated that cerebral microvessels can survive and maintain barrier integrity in areas of the brain that have experienced extensive astrocyte loss (Krum et al, 1997), although these results are in conflict with a more recent study that showed loss and restoration of barrier integrity in vivo following a temporary focal loss of astrocytes (Willis et al, 2004).…”

The capillary bed offers the largest hemodynamic resistance to the cortical blood supply

“…The number of mitochondria, M g ¼ 283, for each glial cell was taken from fractional density data. [70][71][72] The spatial distribution of the glial mitochondria was assumed to lie within a sphere around the nucleus as shown in Figure 6(a). The total rate of metabolized oxygen in each tissue cube depended on the number of mitochondria, which in turn is a function of the anisotropic spatial distribution of neurons and glial cells.…”