Page 52 - Human Lyme Neuroborreliosis

36 David S. Younger

transmitted to perivascular end-feet, was followed by a decrease in vascular
smooth muscle calcium oscillations and arteriolar dilation. The increase in
astrocyte calcium after neuronal activation was in part mediated by activation
of metabotropic glutamate receptors. Calcium signaling in vitro was
influenced by adenosine acting on A2B receptors and by epoxyeicosatrienoic
acids (EET) shown to be synthesized in astrocytes. Moreover, prostaglandins,
EET, arachidonic acid, and potassium ions are candidate mediators of
communication between astrocyte endfeet and vascular smooth muscle.
Astrocytes appear to be capable of transmitting signals to pial arterioles on the
brain surface to ensure adequate blood flow to feeding arterioles, therefore
these cells play an important role in the coupling of dynamic changes in
cerebral blood flow in association with neuronal activity.

Koehler and colleagues [67] have provided insight into the morphological
aspects of neurovascular coupling at the capillary level of the BBB. At least
one astrocyte endfoot process contacts a blood vessel and those abutting
capillaries and larger vessels express connexin-43 and purinergic P2Y
receptors, which together permit Ca2+ increases to be transmitted 60 µm or
more along the abluminal side of the vessel wall. Astrocytic cells are therefore
in a unique position for sensing neuronal activity, integrating that information,
and communicating with blood vessels in brain parenchyma. While neurons do
not directly innervate intraparenchymal vascular smooth muscle, sub-
populations of GABAergic interneurons come into close contact with astrocyte
foot processes and elicit vasodilation. Such neurons might modulate vascular
function through stimulation of nitric oxide (NO) synthase (NOS) activity,
release of vasoactive peptides, or an astrocyte signaling mechanism.

Hudson and coworkers [68] studied trafficking of peripheral blood
mononuclear cells (PBMC) across feline brain endothelial cells (FBEC) in cell
culture system after the addition of combinations of different configurations of
astrocytes and microglia in a model of feline immunodeficiency virus. The
addition of astrocytes to FBEC significantly increased the adherence of PBMC
which was suppressed by the addition of microglia, whereas the latter alone
had no effect on PBMC adherence. Whereas all PBMC showed some level of
trafficking across FBEC, monocytes and B-cells were significantly increased if
astrocytes were present. The exposure of astrocytes notably increased the
percentage of trafficking CD8 T-cells from 24% to 64%, while microglia led
to a significant reversal in the preferential trafficking of CD8 T-cells in the
presence of astrocytes. Astrocytes are capable of secreting various cytokines
and chemokines in the upregulation of adhesion molecules and T-cell ligands
in intact endothelial cells such as ICAM, VCAM, E-selectin, and PECAM.

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