Role of Purine-Converting Ecto-Enzymes in Angiogenic Phenotype of Pulmonary Artery Adventitial Vasa Vasorum Endothelial Cells of Chronically Hypoxic Calves - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 81

[80, 81] further confirmed the importance of coordinated nucleotide-inactivating
cascade for proper immune and cardiovascular functions at various inflammatory,
prothrombotic, and hypoxic states [48, 53, 65, 67].
Strikingly, along with the common view of extracellular ATP as a ligand
for P2 receptors, substrate for ecto-nucleotidases and source of adenosine, this
nucleotide was shown to concurrently serve as a phosphoryl donor for counter-
acting ecto-adenylate kinase and NDP kinase reactions [49, 92]. This backward
ATP-regenerating pathway may represent a principally distinct route for the appear-
ance of extracellular ATP and other purinergic agonists on the cell surface. However,
the implication of these phosphorylating ecto-enzymes in regulation of purinergic
signaling cascade is only beginning to be elucidated. Moreover, the identification
of a complex mixture of soluble purine-converting enzymes freely circulating in
the bloodstream adds another level of complexity to our understanding the regula-
tory mechanisms of purine homeostasis in the vasculature [90, 92]. Additionally,
this may open up further research to assess the potential therapeutic and diagnostic
applications of purinergic enzymes.
5.12 Potential Role of Purine-Converting Enzymes
in Modulating Angiogenic Potential of VVEC
While studies from several laboratories clearly demonstrated the involvement of
exogenous nucleotides in the regulation of vascular angiogenesis and haemosta-
sis, there is a need to further elucidate a signalling role of individual nucleotides
and nucleosides in these responses. In this context, the complexity is created by
co-expression of different receptor subtypes on vascular cells, the respective redun-
dancy of intracellular signalling pathways, as well as the ability of ATP and its
metabolite adenosine to trigger divergent, often opposite, effects on the immune and
mitogenic vascular functions. Moreover, direct quantification of extracellular ATP
is always complicated firstly, due to high turnover sequence: “release-signaling-
inactivation” and secondly, since physiologically relevant levels of this nucleotide
in local tissue environment can substantially differ from bulk concentrations in
the interstitial milieu [91]. Since several enzymatic activities are simultaneously
involved in the active cycling between extracellular ATP and other purinergic
agonists, we hypothesized that vascular remodelling and angiogenesis could be
determined via regulated control of a unique purine-converting enzymatic network
localized to the plasma membrane of vascular cells.
Despite the important regulatory role of extracellular nucleotides on angiogen-
esis, the contribution of ecto-enzymes to endothelial pro-angiogenic phenotype
remains poorly understood. It was demonstrated that significant down-regulation
of ecto-nucleotidase activities on vascular endothelium and other cell types during
chronic hypoxia and oxidative stress was accompanied by triggering nucleotide-
mediated signaling pathways, increased endothelial activation, and concomitant