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in endothelial cells. The authors also reported markedly abnormal angiogenesis in
Cd39-null mice characterized by poor recruitment of surrounding pericytes and
SMCs to new blood vessels. Because embryonic vascular development is normal
in Cd39-null mice [20], the data suggest that purinergic signaling plays differential
roles in physiological blood vessel development as opposed to pathological angio-
genesis. Indeed, in vitro analyses indicated that cell migration in Cd39-null mice
is likely to be secondary to abnormal adhesion and vitronectin receptor function in
Cd39-null endothelial cells. Several members of the integrin family have been impli-
cated in angiogenesis, although the largest body of data has linked the vitronectin
receptor
α
v
β
3
with the promotion of neovascularization [37]. The P2Y
2
R contains
an integrin-binding RGD domain in its first extracellular loop that is required for
P2Y
2
R interactions with
α
v
β
3
integrin [21]. Mutation of the RGD sequence to
RGE decreased the co-localization of
α
v
β
3
integrin with the P2Y
2
R by 10-fold
and greatly impaired UTP-induced phosphorylation of FAK [21]. Direct association
between the P2Y
2
R and
α
v
integrins is necessary for UTP-induced endothelial cell
migration [41], implying an important link between purinergic signaling, integrin
function, and pro-angiogenic cellular behaviors. As discussed above, P2Y
2
R activa-
tion increases osteopontin expression in vascular SMCs. Osteopontin (OPN), one of
the cytokines produced by various tumor cells, is suggested to be involved in angio-
genesis by up-regulating endothelial cell migration in coordination with vascular
endothelial growth factor (VEGF). OPN is secreted from various cancer cell lines
and is postulated to promote malignant transformation [71]. When ras-transformed
fibroblasts were transfected with OPN antisense RNA, their tumorigenic and malig-
nant growth were suppressed significantly [9]. OPN also is overexpressed in
human cancers [13] and serum levels of OPN are substantially elevated in patients
with metastatic cancer [78]. Thus, OPN is postulated to be related with cancer
progression.
Takahashi et al. generated a stable transfectant of murine neuroblastoma C1300
cells that constitutively secretes high levels of murine OPN [79]. To demonstrate the
effect of OPN on tumor-induced angiogenesis in vivo, Millipore chambers contain-
ing OPN-transfected or control cells were implanted in the dorsal air sac of mice.
The OPN-transfected cells significantly induced neovascularization in comparison
to the control cells in mice, thus providing direct evidence for OPN involvement in
tumor angiogenesis.
Our data link P2Y purinergic receptor signaling to mechanisms controlling the
expression of a cell adhesion molecule involved in monocyte/lymphocyte recruit-
ment. Therefore, up-regulation of P2Y receptors may be a potential diagnostic
indicator for the early stages of atherosclerosis. We also demonstrated for the first
time that the P2Y
2
R can mediate activation of VEGFR-2 and directly link nucleotide
receptor activation to an established tumor angiogenesis signaling pathway. Thus,
particular effort must be made to understand the consequences of nucleotide release
from cells in the cardiovascular system and the subsequent effects of P2 nucleotide
receptor activation in blood vessels, which may reveal novel therapeutic strategies
for atherosclerosis, restenosis after angioplasty and angiogenesis.
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