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pig, rat, mouse, rabbit and sheep, originating from different vascular beds, i.e.,
umbilical vein [28], coronary artery [106], aorta [117], pulmonary artery [112],
pulmonary artery VVEC [47], corneal vessels [49], uterine artery [123], brain cap-
illary [110], renal artery [65], retinal microvasculature [114], and saphenous vein
[34]. However, in these ECs, different purinergic effects and signaling pathways
were studied, making comparisons of the results difficult. Therefore, effects of
extracellular nucleotides in these different ECs should be systematically evaluated.
The outcomes of purinergic signaling in the endothelium also need further
evaluation. We demonstrated that nucleotide-induced activation of FAK/Pax/p130
and up-regulation and transactivation of integrin
α
v
were followed by cytoskeletal
changes and PI3K-dependent EC migration, indicating that P2 receptors may be
involved in the regulation of angiogenesis. Some other data demonstrating puriner-
gic activation of mTOR, PI3K/Akt and ERK, pathways implicated in cell growth,
survival, migration and proliferation, support this hypothesis [47]. However, con-
trary to numerous in vitro and in vivo data showing that nucleotides increase SMC
proliferation, similar data for ECs are missing. Our own (unpublished) data indi-
cate that depending on the EC type and experimental conditions, nucleotides can
stimulate, inhibit or have no effect on EC proliferation.
A role for purinergic signaling in EC apoptosis, postulated to contribute to vas-
cular injury or the regulation of angiogenesis, also awaits additional study, as not
much data are available on this subject. Adenosine, but not ATP or ADP, has been
shown to induce apoptosis in pulmonary artery ECs by increasing intracellular S-
adenosylhomocysteine levels and impairing methylation of some proteins or nucleic
acids [33, 98]. In another study suggesting that ATP and ADP induce EC apopto-
sis, very high levels of ATP were used (10 mM) to induce cell death, whereas 100
μ
M and 1 mM ATP had no effect on EC apoptosis [119]. Moreover, in this report,
high concentrations of ATP and ADP activated NF
B, whereas in ECs this pathway
exerts anti-apoptotic effects [52]. Again, the role of nucleotides in EC apoptosis has
to be further investigated.
Our data indicate that extracellular nucleotides induce rapid and transient activa-
tion of eNOS, AMPK, and mTOR/p70S6k and a delayed increase in ATPi. However,
some of these data are not consistent,
i.e.
, activation of AMPK should turn-off the
mTOR pathway, which is energy-dependent.
EC activation and damage are associated with blood coagulation, inflamma-
tory responses (e.g., up-regulation of adhesion molecules), endothelial dysfunction
(e.g., reduced NO generation), and atherosclerotic lesion development (e.g., neoin-
tima formation). Hyperglycemia/diabetes mellitus and hypertension are conditions
that negatively affect vascular function. Therefore, nucleotide-induced activation of
eNOS and AMPK may exert protective effects in some vascular-related diseases.
This hypothesis needs further validation.
Although the multiple functions of eNOS/NO in ECs are well established, and we
showed that extracellular nucleotides activate eNOS, outcomes associated with NO
generation induced by extracellular nucleotides should be confirmed. We expect to
verify that P2 receptor signaling via NOmay protect ECs from high glucose-induced
apoptosis, attenuate cytokine-mediated up-regulation of pro-inflammatory proteins
or reduce oxidative stress.
κ
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