The P2Y2 Nucleotide Receptor in Vascular Inflammation and Angiogenesis - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 63

induces increases in osteopontin mRNA expression by increasing both osteopontin
mRNA stabilization and osteopontin promoter activity [64]. Recent studies have
shown that activation of an AP-1 binding site located 76 bp upstream of the
transcription start site in the rat osteopontin promoter is involved in UTP-induced
osteopontin expression [65].
The ability of extracellular nucleotides to act as chemoattractants for rat arte-
rial SMCs in a concentration range potentially found in vessels under pathological
conditions [16] and the findings of previous studies demonstrating the mitogenic
activity of extracellular nucleotides for these cells [22, 23, 52, 86] suggest that
nucleotides released from mechanically-stretched or damaged vascular cells during
angioplasty therapy for occluded arteries may promote angiogenesis.
4.2.3 P2Y 2 Receptors in Tumor Angiogenesis
Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleo-
side diphosphate kinase (NDPK) has been recently described [68]. These authors
showed that MDA-MB-435S human breast cancer cell-secreted NDPK-B supports
tumor formation by modulating the local ATP concentration thereby activating
endothelial cell P2Y receptor-mediated angiogenesis. Their model suggests an
NDPK-dependent recycling of ADP back to ATP in both arteries and capillaries.
NDPK in the arteries may elevate local ATP concentrations to produce P2YR-
mediated vasodilation and inhibit ADP-dependent platelet aggregation, mechanisms
advantageous to the transit of cancer cells to secondary sites. NDPK secretion in
capillaries may elevate local nucleotide concentrations and produce P2Y nucleotide
receptor-mediated angiogenesis. We have previously shown that the P2Y 2 R can
mediate transactivation of VEGFR-2 [74] and directly link nucleotide receptor acti-
vation to an established tumor angiogenesis signaling pathway (VEGF-VEGFR
signaling). P2Y receptor potentiation of VEGFR-2 signaling, therefore, may be
essential for manifestation of the angiogenic properties of nucleotides such as ATP.
P2Y and VEGF receptors are colocalized to caveolar domains in the cell mem-
brane, which could propagate a substantial pro-angiogenic signal in response to
small amounts of receptor agonist [43].
Jackson et al. have reported that disordered purinergic signaling inhibits patho-
logical angiogenesis in Cd39/Entpd1-null mice [40]. CD39/ecto-nucleoside triphos-
phate diphosphohydrolase-type-1 (ENTPD1) is the dominant vascular ectonucleoti-
dase that catalyzes the phosphohydrolysis of extracellular nucleotides in the blood
and extracellular space. This ecto-enzymatic process modulates endothelial cell,
leukocyte, and platelet purinergic receptor-mediated responses to extracellular
nucleotides. These authors reported that deletion of Cd39/Entpd1 results in abroga-
tion of angiogenesis, causing decreased growth of implanted tumors and inhibition
of pulmonary metastases. These changes were associated with decreased activation
of focal adhesion kinase (FAK) and extracellular signal-regulated kinase-1 and -2