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-induced
stimulation of the stress-activated protein kinases, JNK, p38, and its downstream
target, MAPKAP kinase-2, which was mediated by Ca
2+
-independent isoforms
of PKC. These results reveal a novel cross-talk between P2Y receptors and the
TNF
In the EAhy926 EC line, UTP, ATP, but not UDP, inhibited TNF
α
-stimulated p38 pathway in ECs [87].
Interaction between P2Y receptors and VEGF signaling pathways has been
also documented [107]. Activation of the P2Y2 receptor with its ligand, UTP, up-
regulated the expression of pro-inflammatory vascular cell adhesion molecule-1
(VCAM-1) in human coronary artery ECs (HCAECs). This effect of UTP was medi-
ated via P2Y2 receptor-dependent phosphorylation of VEGF receptor-2 (VEGFR-2)
and activation of its signaling pathway with involvement of Src homology-3-binding
sites in the C-terminus of the P2Y2 receptor. The small GTPases Rho (RhoA)
were implicated in this pathway, as a dominant negative form of RhoA inhibited
P2Y2 receptor-mediated VCAM-1 expression. Moreover, it was established that
VEGFR-2 and the P2Y2 receptor co-localize upon UTP stimulation.
In another study, Rumjahn et al. demonstrated that activation of P2Y receptors
promotes EC angiogenesis. Activated P2Y1 receptors transactivate VEGFR-2 in the
absence of VEGF, which stimulates EC tubulogenesis. This P2Y1 receptor-VEGFR-
2 interaction and resulting signal transduction may affect vascular homoeostasis and
tumor-mediated angiogenesis [100].
Interplay between P2Y receptor-induced signaling and growth factor receptor
has been reported to modulate activity of MAPK. Specifically, it was documented
that UTP transiently activated ERK in PC12 cells via P2Y2 receptor-mediated
transactivation of the epidermal growth factor receptor, downstream at the level
of the related adhesion focal tyrosine kinase (RAFTK) [111]. It remains to be
determined if similar cross-talk between tyrosine kinases and purinergic receptors
signaling exists in ECs.
There is also evidence of cross-talk between P2Y2 receptors and integrins [8, 43,
62]. This interaction affects cell chemotaxis and migration and therefore might be
associated with regulation of angiogenesis by nucleotide-induced signaling.
On the basis of established data, we hypothesize that purinergic signaling may
influence other signaling pathways. One of the novel roles of AMPK is to prevent
the activation of NF-
α
κ
B in ECs exposed to the fatty acid palmitate or the cytokine
α
κ
TNF
B activation and VCAM-1 expression induced by
palmitate were markedly inhibited by AICAR, the AMPK activator, and by expres-
sion of a constitutively active AMPK [21]. The mechanism responsible for this
observation remains to be elucidated, however it is possible that interplay between
extracellular nucleotide-induced activation of AMPK and the TNF/NF-
. The increases in NF
B signal-
ing pathway could play a role in the anti-inflammatory effects of purines in the
endothelium.
Likewise, NO exerts anti-inflammatory effects in cytokine-stimulated human
saphenous vein endothelial cells, by inhibiting NF
κ
B-mediated up-regulation of
VCAM, E-selectin and to some extent, ICAM-1 [34, 88]. Therefore, we predict that
extracellular nucleotides by activation of eNOS and induction of NO generation
may negatively affect the NF
κ
κ
B signaling pathway.
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