The P2Y2 Nucleotide Receptor in Vascular Inflammation and Angiogenesis - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 62

adequate to nourish the inner media and intimal layers. As vessel wall thickness
increases in the setting of vascular disease, proliferation of the vasa vasorum and
intimal neovascularization is observed.
The recruitment of pericytes and vascular smooth muscle cells (VSMCs) to
endothelial tubes plays a key role in angiogenesis. These mural cells stabilize
nascent endothelial tubes and therefore are essential for the formation of functional
vessels [4].
Many growth factors have been suggested to play pivotal roles in different aspects
of neovascularization. For instance, platelet-derived growth factor (PDGF) induces
differentiation of mesenchymal cells into pericytes and VSMCs and stimulates the
migration of these cells to the newly formed vessels [34, 36, 49, 80]. However, little
is known about the contribution of extracellular nucleotides and their receptors to
neovascularization.
4.2.2 Chemotactic Effects Mediated by P2Y 2 Receptors
In cultured endothelial cells (CECs) from guinea pig cardiac vasculature, both
UTP and vascular endothelial growth factor (VEGF) are significant mitogenic and
chemotactic factors [69]. In chick chorioallantoic membranes (CAMs), UTP and
VEGF produced statistically significant increases in CAM vascularity [69]. Given
the lack of selective ligands for receptors that bind UTP, these authors were unable
to definitively identify the receptors mediating mitogenic or chemotactic responses
to UTP in cultured endothelial cells or the receptor(s) that are responding to UTP
by promoting angiogenesis in chick CAMs. However, the existence in CECs of
two receptors capable of responding to UTP (P2Y 2 R and a UTP-selective receptor)
has been previously reported [90]. Recent studies indicate that the extracellular
nucleotides ATP, ADP, UTP and UDP serve as directional cues for the migration of
rat aortic SMCs [14]. Nucleotide-induced migration of SMCs is the consequence
of both chemotaxis and chemokinesis and may result from the activation of one or
more P2 nucleotide receptor subtypes. The ability of UTP at submicromolar levels
to stimulate migration of SMCs supports the hypothesis that this response could
have physiological consequences and is mediated by P2Y 2 receptor activation
without excluding participation of other P2Y receptor subtypes. The increased
migration of SMCs in response to extracellular nucleotides could be related to
increases in extracellular matrix (ECM) protein expression. Indeed, previous
studies have shown that UTP induces osteopontin expression in rat and rabbit aortic
SMCs [26, 73]. Increased expression of osteopontin, an arginine-glycine-aspartate
(RGD)-containing ECM protein, is associated with the activation of rat arterial
SMCs in vitro and in vivo [26, 52, 73]. The increase in osteopontin expression
plays a key role in UTP-induced migration of rat aortic SMCs, since a monoclonal
antibody against osteopontin fully abolished UTP-induced migration [62], whereas
an antibody against vitronectin, another ECM protein also involved in migration
of human SMCs [19], had no effect on the migration of rat aortic SMCs [62]. UTP