Page 50 - Human Lyme Neuroborreliosis

34 David S. Younger

histochemical stain. The number of granular lysosomes in brain pericytes
increases with disruption of the BBB. Several other markers have been
employed in the identification of pericytes including, smooth muscle ?-actin
(SMA), desmin, polydendrocytes (NG2 cells), platelet-derived growth factor
receptor (PDGFR)-?, aminopeptidase A and N, regulator of G-protein
signaling 5 (RGS5) and the promoter trap transgene XlacZ4 [51].

An active role of pericytes in the BBB was inferred from the localization
of ?-glutamyl transpeptidase (GGTP) in brain capillary endothelial cells and
pericytes, both in vivo and in vitro [52]. This heterodimeric glycoprotein
distributed on the external surface of the cell catalyzes the transfer of ?-
glutamyl from glutathione to accept peptides and functionally appears to be
concerned with transport of large neutral amino acids across the BBB.
Detectable amounts of GGTP are found in other regions of the brain with an
intact BBB but not in those that lack one such as the median eminence.
Abnormal platelet derived growth factor (PDGF)-B and PDGF-? signaling
plays a critical role in the recruitment of pericytes to newly formed vessels,
and when deficient, as in knockout of pdgfb and pdbfrb, leads to perinatal
death due to vascular dysfunction with associate vascular leakage and
hemorrhage.

Pericyte-endothelia cell signaling factors have been identified.
Sphingosine-1-phosphate (SIP) signaling triggers cytoskeletal, adhesive, and
junctional changes, affecting cell migration, proliferation, and survival [53].
Angiopoietin-Tie2 signaling in the vascular wall involved in reciprocal
communication between endothelial cell and pericytes, such as may be seen in
ang1- or tie2-null mice deficient in Ang1, which leads to defective
angiogenesis and poorly organized BM and reduced coverage and detachment
of pericytes. Conversely, overexpression of Ang1 leads to expanded and
stabilized, leakage resistant microvasculature [54, 55].

The importance of CNS pericytes has been underscored by their proposed
role in neuroimmunological networks associated with BBB function. First,
CNS pericytes may be actively involved in the regulation of leukocyte
transmigration, antigen presentation, and T-cell activation. They constitutively
express low levels of VCAM-1 and ICAM-1, which have costimulatory
activity in main histocompatibility cell (MHC)-class II dependent antigen
presentation; and leukocytes cluster on pericytes in culture [43] suggesting a
role in inflammation. Smooth muscle pericytes present antigen in vivo and
differentially activate Th1 and Th2 CD4-T cells. Moreover CNS pericytes
produce a number of immunoregulatory cytokines including interleukins (IL)
and granulocyte-macrophage (GM) colony stimulatory factor [56].

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