Biology Reference
In-Depth Information
Chapter 4
The P2Y
2
Nucleotide Receptor in Vascular
Inflammation and Angiogenesis
Cheikh I. Seye and Gary A. Weisman
Abstract
There is compelling evidence for increased neovascularization of blood
vessel walls at sites of intimal hyperplasia in models of arterial stenting, angio-
plasty, and venous bypass graft failure. We have shown that activation of the
P2Y
2
nucleotide receptor (P2Y
2
R) in vascular endothelial cells in vitro induces
VCAM-1 (vascular cell adhesion molecule-1) expression and promotes the adher-
ence of monocytes. VEGF, a pleiotropic factor that regulates endothelial cell
survival, proliferation, and migration through its interaction with two receptor tyro-
sine kinases, Flt-1 or VEGF receptor-1 and Flk-1/KDR or VEGF receptor-2 also
stimulates the expression of VCAM-1 in endothelial cells. Interestingly, our stud-
ies indicate that P2Y
2
R activation promotes the VEGF-independent activation of
Flk-1/KDR via Src binding to Src homology (SH3) binding domains in the C-
terminal tail of the P2Y
2
R leading to the up-regulation of VCAM-1. The P2Y
2
R
also contains an arginine-glycine-aspartate domain that mediates interactions with
α
v
β
3
/
β
5
integrins that enable nucleotides to increase cell migration, an important
event in inflammation and tumor angiogenesis. Taken together, these findings indi-
cate that P2Y
2
Rs can stimulate multiple signaling pathways to promote a variety
of pathological responses underlying chronic inflammation, angiogenesis in tumors
and atherosclerosis.
Keywords
Nucleotide
·
P2Y
2
receptor
·
Endothelial cell
·
Inflammation
·
Atherosclerosis
·
Adhesion
·
Migration
·
Angiogenesis
·
Proliferation
·
Artery
·
Smooth muscle cell
·
G protein
·
Monocyte
·
Tyrosine kinase
·
Calcium
·
Microvessels
B
C.I. Seye (
)
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635
Barnhill Drive, MS 332, Indianapolis, Indiana 46202
e-mail: cseye@iupui.edu
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