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non-vascular cells including monocytes. Recent work demonstrates that in endothe-
lial cells ATP- and UTP-induced stimulation of P2Y2 receptors is associated with
co-activation of VEGF receptor-2, expression of Vascular Cell Adhesion Molecule-
1 (VCAM-1), and monocyte recruitment, implying a link between purinergic
signaling, angiogenesis and inflammatory responses [75, 76]. The product of ATP
hydrolysis, adenosine, has also been shown to induce proliferative responses in
various types of endothelial cells [24, 25, 30, 34]. Importantly, ATP acts synergis-
tically with cytokines (e.g. platelet-derived growth factor, epidermal growth factor,
and insulin-like growth factor) and integrins to stimulate vascular cell proliferation
and migration, thereby supporting the physiological relevance of extracellular ATP
under hypoxic and stress-related conditions [23, 28, 37, 42]. Recent findings also
demonstrate a role of extracellular ATP and UTP in the stimulation and migration
of human hematopoietic stem cells in vitro and in vivo [51, 70]. Together, these
studies emphasize the angiogenic potency of extracellular adenine and pyrimidine
nucleotides and their role in the regulation and modulation of vascular cell func-
tion during disease processes. However, despite the considerable progress in the
understanding of the molecular and cellular mechanisms involved in the control
of neovascularization as well as the continued interest in pro-angiogenic factors
in various pathologic and physiologic states, including hypoxia and inflammation,
the role of extracellular nucleotides in hypoxia-induced endothelial angiogene-
sis and the concomitant changes in microvascular phenotype is recently gaining
appreciation.
5.8 Extracellular ATP and Pulmonary Artery Adventitia
Previously, we demonstrated that hypoxia stimulates release of ATP from adventi-
tial fibroblasts and that this exogenous ATP acts in an autocrine manner to stimulate
cell proliferation, a response critical in the vascular remodeling process observed in
response to hypoxic conditions [28, 79]. These observations support the idea that
in addition to nerve and circulating blood cells, vascular cells themselves appear
to be potent sources of ATP and other adenine nucleotides [12, 29]. These obser-
vations prompted us to evaluate endothelium of newly formed adventitial vasa
vasorum as a potential, yet unidentified, source of extracellular ATP in the pul-
monary artery vessel wall. Indeed, our studies demonstrated that PA adventitial
VVEC release ATP in response to hypoxia and low osmolarity, suggesting these
cells may represent a potent source of extracellular ATP within the pulmonary
artery vascular wall and that extracellular ATP could contribute to vasa vasorum
neovascularization [79]. These observations support the notion that local purinergic
signaling networks can be initiated by hypoxic stress, which in turn alter endothe-
lial cell phenotype and function. In addition, since vascular cells express multiple
purinergic receptors, extracellular nucleotides may play as an intercellular sig-
naling molecule, providing cell-to-cell communication by an autocrine/paracrine
mechanism.
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