Page 51 - Human Lyme Neuroborreliosis

The Blood-brain Barrier 35

Transforming growth factor (TGF)-? produced in an active form in
pericytes/endothelial cocultures, may function as an endogenous
immunoregulator at the BBB [57]. It is therefore of interest that TFG-??
inhibits cytokine-induced CNS endothelial cell activation in isolated rat CNS
microvessels [58]. To further emphasize the importance of pericyte
interactions in association with endothelial cells, there are no known genetic
human diseases due to pericyte deficiency.

Astrocyte Interactions

The intimate relationship of astrocytes and blood vessels was appreciated
by Cajal [59] and Golgi [60] in the late nineteenth century. Since then,
ultrastructural studies have shown that astrocytic endfeet in the perivascular
astroglial sheath leads to a complete covering of brain microvessels [61].
Signaling at the gliovascular interface is facilitated by astrocyte-specific
proteins and channels in astrocyte endfeet including, acquaporin-4, connexin
43, purinergic receptors, and potassium channels [62]. Moreover, ultra-
structural studies have demonstrated that processes of vasoactive neurons for
the regulation of cerebrovascular tone, in particular those expressing
noradrenaline, synapse onto astrocytes rather than directly onto blood vessels
[63]. Altogether, these findings support the observation that astrocytes, one of
the more numerous cells in the CNS, are important determinants of the intact
BBB and crucial as well for ionic homeostasis, neurotransmitter uptake,
synapse formation, and neurodevelopment. Zhang and Barres [64] have
reviewed the differences in astrocyte morphology, developmental origin, gene
expression profile, physiological properties, function and response to injury
and disease. Two essential roles of astrocytes, in neurovascular coupling and
the regulation of lymphocyte trafficking across the BBB have been extensively
studied.

All signaling molecules targeted to the cerebral vasculature must first act
on or pass through astrocytes in order to reach smooth muscle cells in the
vessel wall. It is now recognized that neurotransmitter-mediated signaling has
a key role in regulating cerebral blood flow, and that much of this control is
mediated by astrocytes [65], moreover, cerebral blood flow may be controlled
by capillaries as well as by arterioles. The glial and neuronal control of
cerebral blood flow has been studied in brain slices [66]. Koehler and
colleagues [67] demonstrated that electrical field stimulations in brain slices
led to an increase in intracellular calcium in astrocyte cell bodies which when

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