The P2Y2 Nucleotide Receptor in Vascular Inflammation and Angiogenesis - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 55

4.1 Role of P2Y 2 Receptors in Vascular Inflammation
4.1.1 Introduction
Extracellular nucleotides cause a wide range of cellular responses and appear to
play a role in the regulation of many vascular functions [63]. Vascular cells release
nucleotides in response to ischemia, hypoxia, and chemical or mechanical stress
[2, 10, 15, 58]. Other sources of extracellular nucleotides include aggregating
platelets, degranulating macrophages, and excitatory neurons [12, 61]. Release of
nucleotides has been proposed to occur by exocytosis of ATP/UTP-containing vesi-
cles, facilitated diffusion by putative ABC transporters, cytoplasmic leakage, and
electrodiffusional movements through ATP/nucleotide channels [92]. It is becom-
ing apparent that extracellular nucleotides can promote the development of a variety
of pathologies including disorders of the immune system and neurodegenerative and
vascular diseases [88]. Indeed, ATP or UTP induces proliferation and migration of
vascular smooth muscle cells, two processes involved in the development of inti-
mal lesions found in atherosclerosis and post-angioplasty restenosis. The biological
effects of extracellular nucleotides are mediated through activation of P1 and P2
purinergic receptors. P2 receptors are subdivided into two distinct categories, the
metabotropic G protein-coupled (P2Y) receptors and ionotropic ligand-gated chan-
nel (P2X) receptors [57]. Vascular cells have been shown to express metabotropic
P2Y and ionotropic P2X receptors [63].
Vascular diseases such as atherosclerosis and post-angioplasty restenosis are
initiated by vascular injury. Previous reports demonstrate that large amounts of
nucleotides are released into the extracellular milieu in response to vascular stress
conditions, including ischemia/oxidative stress, flow, and mechanical stretch [32,
60]. In addition, high concentrations of extracellular ATP and UTP generated
in vivo by platelet aggregation or cell damage that occurs during transluminal
angioplasty likely increase the concentration of nucleotides in the vessel wall.
Although the metabolism of extracellular nucleotides by ecto-nucleotidases plays
a role in the regulation of purinergic signaling, recent studies indicate that chronic
hypoxic exposure of pulmonary artery endothelial cells can decrease the rate of
ecto-nucleotidase activity [28]. In addition, it has been reported that endothelial
cell activation can decrease ATP-diphosphohydrolase activity [66], suggesting that
pathological conditions affecting blood vessels contribute to local elevations in
nucleotide concentrations in the vessel wall.
4.1.2 P2Y 2 Receptor Up-Regulation and Endothelial Expression
of Adhesion Molecules: Role in Endothelial Inflammation
P2Y 2 R up-regulation occurs in various models of vascular injury including bal-
loon denudation of the rat aorta [72], placement of a silicone collar around a rabbit
carotid artery [73] and stenting of the pig coronary artery [77]. In the collared rabbit