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P2X (ionotropic) purinergic receptors, whereas the effects of adenosine are medi-
ated through A1, A2A, A2B and A3 receptors [2, 11, 20]. The wide tissue
distribution of purinergic receptors together with the expression of multiple recep-
tor subtypes in vascular cells point to the physiological importance of purinergic
signaling system for the regulation of vascular cell function. It is also becoming
evident that alterations in the physiology of purinergic signaling may result in the
development of a variety of neurogenerative, immune, and vascular pathologies
[12, 19]. Considering this, by targeting purinergic receptors with specific ligands
(either agonists or antagonists) would provide a useful tool for directional manipula-
tion of pathway-specific intravascular responses associated with various pathologic
conditions.
5.6 Sources and Potential Mechanisms of ATP Release
into the Extracellular Milieu
Extracellular ATP concentrations are thought to be elevated in the local tissue
microenvironment at various physiological and pathological conditions including
hypoxia, inflammation, fluid shear stress, low osmolarity, thrombosis, and sym-
pathetic stimulation (when ATP is co-released with noradrenalin), [8, 9, 10, 28,
39, 47]. It is also known that extracellular nucleotides are released in response
to mechanical forces and other environmental stresses such as osmotic shock,
acidosis, hyperoxia and hypoxia by cells of the vasculature, airways, and gut
and play a key role in transducing cellular responses via activation of puriner-
gic receptors in these organs [11, 50, 63]. Furthermore, along with transient
release of nanomolar or sub-micromolar ATP concentrations in response to vari-
ous stimuli, the cells can also constitutively release ATP at certain basal rates and
maintain pericellular ATP levels in their vicinity within a high micromolar range
[2, 91].
5.7 Implication of Extracellular ATP for Vascular Diseases
A number of studies support the idea that extracellular nucleotides could contribute
to the development of vascular disease. Extracellular ATP has been implicated in
the hyperplasia and hypertrophy of arterial walls in spontaneously hypertensive rats
[66], the regulation of vascular permeability [40, 45, 62] and the control of pro-
liferation and migration of vascular smooth muscle cells and hematopoietic stem
cells [42, 51, 70, 72]. Purinergic antithrombotic drugs have been shown to reduce
the risk of recurrent strokes and heart attacks [12]. Extracellular ATP and UTP
have been demonstrated to stimulate DNA synthesis in vascular endothelial cells,
smooth muscle cells (SMC), and adventitial fibroblasts [23, 28, 83]. In addition,
extracellular nucleotides appear to directly affect migration of vascular as well as
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