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to cytokine-activated microvascular endothelium that facilitates pro-inflammatory
monocyte migration across the blood-brain barrier. Indeed, increased monocyte
migration across human brain endothelium is augmented by A
, and monocyte
adherence and transendothelial migration are inhibited by antibodies to the putative
A
β
receptor for advanced glycated endproducts (RAGE) or the platelet endothelial
cell adhesion molecule (PECAM-1) [29, 30]. Under normal conditions, the vascular
endothelium maintains blood fluidity and provides a barrier separating blood cells
and plasma factors from highly reactive elements in the underlying tissue [53, 67].
Quiescent endothelial cells produce substances to maintain vascular homeostasis
[24, 35, 48, 53]. However, injury or stress in surrounding tissue can shift endothe-
lial cells from a quiescent to a pro-inflammatory status, largely due to the increased
release of cytokines. Besides A
β
, other factors that can induce a pro-inflammatory
status in endothelium include obesity, hypertension, diabetes, cigarette smoking,
high serum LDL or homocysteine levels, chronic viral or bacterial infections, endo-
toxaemia, and an unfavorable genetic background [18]. Thus, stress-induced injury
to the vasculature and underlying tissue would be expected to contribute similarly to
the development of chronic inflammation under pathological conditions, including
Alzheimer's disease, atherosclerosis and cancer. Interestingly, recent results indicate
that cytokine-induced P2Y
2
R up-regulation and activation in primary rat cortical
neurons promotes metalloprotease-dependent non-amyloidogenic peptide release
(see Fig. 4.1), rather than A
β
formation [45], suggesting that modulation of P2Y
2
R
activity in Alzheimer's disease may be a useful therapeutic approach for limiting
chronic inflammatory and neurodegenerative responses.
β
4.1.4 Development of Transgenic Rats Overexpressing the P2Y
2
Receptor: A Model to Study Inflammatory Diseases
Recently, we developed a transgenic (Tg) rat model overexpressing the P2Y
2
R
[1]. We demonstrated that incorporation of the P2Y
2
R transgene into a lentivi-
ral vector enabled stable P2Y
2
R mRNA expression through 6 generations and the
expressed P2Y
2
R was functionally active, as indicated by increased P2Y
2
R agonist-
induced intracellular calcium mobilization in single smooth muscle cells (SMCs)
from P2Y
2
R overexpressing Tg rats, as compared to wild type (WT) rats. In addi-
tion, there was a significant increase in the percentage of responsive aortic SMCs
from P2Y
2
R overexpressing Tg rats, versus WT rats. We found that P2Y
2
R over-
expressing Tg rats express increased levels of P2Y
2
R mRNA in major organs and
tissues, including aorta, brain, heart, kidney, liver, lung, lacrimal gland and leg mus-
cle. Comparisons of WT and P2Y
2
R overexpressing Tg rats showed that expression
levels of the P2Y
2
R transgene in tissues did not change between the third and sixth
generations. The endogenous P2Y
2
R in WT rats is expressed in liver, lung and
muscle and to a lesser extent in heart, kidney, and brain, but was undetectable in
lacrimal and salivary glands. Expression of the P2Y
2
R transgene in lacrimal and
salivary glands of P2Y
2
R overexpressing Tg rats was elevated as compared to WT
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