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Fig. 5.6 Schematic view of the role of extracellular nucleotides in angiogenic phenotype of
endothelial cells. Stress conditions such as hypoxia, inflammation and oxidative stress result
in endogenous release of ATP (from both circulating cells and vascular wall) and in subse-
quent activation of endothelial cells towards pro-angiogenic phenotype characterized by decreased
ATP/ADP-hydrolyzing and increased ATP-regenerating activities. Elevated levels of extracellu-
lar nucleotides (ATP and ADP) induce mitogenic, migratory and morphogenetic responses in
EC. The effects of hypoxia on angiogenic activation of endothelial cells can be reversed by
upregulation (down-regulation) of ecto-nicleotidase activities (ecto-ATPase/ADPase (CD39) and
ecto-5 -nucleotidase (CD73) resulting in accumulation of extracellular adenosine
and MVEC over the activities in VVEC. However, ecto-5 -nucleotidase activ-
ity in MPAEC was almost equivalent, and in MVEC it was slightly lower than
ecto-5 -nucleotidase activity observed in VVEC. In turn, VVEC exhibited sig-
nificantly higher levels of AK and NDPK activities compared to MPAEC and
MVEC. Interestingly, recent findings on the co- expression of counteracting ATP-
regenerating ectoenzymes in the lymphoid cells suggest that regulation of purine
metabolism might extend beyond the inactivating pathways. Specifically, along with
low ecto-nucleotidase and high ADA activities, the lymphoid cells are characterized
by relatively high ecto-AK and NDP kinase activities [90] and in addition, are capa-
ble of maintaining micromolar “ATP halo” in their immediate vicinity [91]. It is
speculative that “ATP-regenerating” phenotype of hypoxic VVEC may resemble a
phenotype of some circulating blood cells and could represent a novel mechanism
of hypoxia-induced endothelial angiogenesis.
5.13 Conclusion and Perspectives
We demonstrated that extracellular nucleotides are both important angiogenic
signaling molecules, and play an important physiological role in controlling
angiogenic properties of vasa vasorum endothelial cells. Pathological conditions
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