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 80

in endothelial cells isolated from PA and aorta, along with a negligible angiogenic
effects by ATP in these cells [29]. Together, these observations further support the
idea that VVEC are distinct in their ability to proliferate in response to extracellular
ATP. Therefore it can be speculated that VVEC isolated from the sites of hypoxic PA
adventitia, may therefore have unique phenotypical characteristics, with a particu-
lar reliance on extracellular nucleotides as an environmental stimuli. In conjunction
with other reports, our data suggest that there must be tremendous heterogeneity in
endothelial phenotypes, with regard to extracellular nucleotide-induced functional
responses and the signaling pathways through which these effects are mediated.
5.11 Purine-Converting Ecto-Enzymes and Their Role
in the Regulation of Vascular Homeostasis
Subsequent to signal transduction, extracellular nucleotides need to be rapidly
inactivated. The duration and magnitude of purinergic signaling in target cells
is governed by a network of membrane-bound and soluble enzymes. General
schemes of purine metabolism have included a role for the purine-inactivating
enzymes of ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) fam-
ily, ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP) family, ecto-5 -
nucleotidase/CD73 and adenosine deaminase [91, 92]. The initial steps of ATP and
ADP hydrolysis in the vasculature are primarily mediated by the enzymes known
as ecto-ATPase, ATPDase, apyrase etc., which, according to the current nomen-
clature, should be termed as NTPDase family members and classified in order of
discovery and classification [69]. Namely, eight different ENTPD genes encode
members of the NTPDase protein family, with four of them (NTPDase1,2,3,8)
being expressed as cell surface-located enzymes. NTPDases 5 and 6 exhibit intra-
cellular localization and undergo secretion after heterologous expression, while
NTPDases 4 and 7 are entirely intracellularly located, facing the lumen of cytoplas-
mic organelles. Subsequent breakdown of ATP/ADP-derived AMP into adenosine
is mediated by another nucleotide-inactivating enzyme, ecto-5 -nucleotidase/CD73,
which is anchored to the plasma membrane by glycosyl-phosphatidylinositol and
expressed to a variable extent in vascular and other tissues [38, 69, 91, 92, 94].
In terms of the vascular system, endothelial E-NTPDase1/CD39 in conjunc-
tion with ecto-5 -nucleotidase/CD73, have been implicated in playing a critical
role through the termination of prothrombotic and proinflammatory effects of
circulating ATP and ADP and their conversion into adenosine. This keeps the
haemostatic process tightly regulated by preventing excessive clot formation and
vessel occlusion [53, 55, 69]. In addition, selective up-regulation of the CD39-CD73
axis on the surfaces of activated CD4 + CD25 + Foxp3 + T-regulatory cells comprises
an important constituent of their immunosuppressive machinery via sequential
breakdown of lymphotoxic and proinflammatory ATP into anti-inflammatory adeno-
sine, thus inhibiting T cell proliferation and secretion of cytokines [18, 33, 77].
Studies with mice lacking E-NTPDase-1/CD39 [57] or ecto-5 -nucleotidase/CD73