Stimulation of Wound Revascularization by Adenosine Receptor Activation - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 93

pharmacological vasodilator dipyridamole that inhibits the activity of adenosine
deaminase and adenosine re-uptake, elicits a neovascular response in rat cardiac and
skeletal muscle, strongly supporting a role for adenosine in promoting angiogenesis
[10]. We will review the mechanisms by which adenosine receptor activation affects
the function of microvascular endothelial cells implicated in wound revasculariza-
tion and will discuss the contribution of the adenosine receptors to blood vessel
formation.

6.2 Adenosine Receptor Expression and Function on Dermal
Microvascular Endothelial Cells

Most of our knowledge of the effects of adenosine receptors activation on endothe-
lial cells: down-regulation of cytokine-induced adhesion molecules expression;
increased vascular barrier; promotion of migration and proliferation; signal trans-
duction mechanisms comes from experiments carried out using endothelial cells

from multiple origins, and mainly human umbilical vein (HUVEC). However, it
should be taken in consideration that endothelial cells are exposed to particular
physico-chemical and immunological condition depending on the vascular bed of
origin, therefore phenotypical differences are expected [1, 49].
In most blood vessels, adenosine is a potent vasodilator via activation of A 2A
and/or A 2B receptors, expressed in both the endothelium and smooth muscle.
Conversely, adenosine is a potent vasoconstrictor in some branches of the pul-
monary arteries and in renal afferent arterioles, through smooth muscle A 1 receptor
activation [56]. Several expression profiling and functional studies have revealed
that endothelial cells from multiple origins do not express A 1 and A 3 recep-
tors [5, 14, 42]. Microvascular endothelial cells, in particular, play a central role
in inflammation by recruiting circulating leukocytes to tissues, in part through
cytokine-regulated expression of endothelial-leukocyte adhesion molecules that
differ from large vessel endothelial cells [32, 45, 57].
The expression pattern of A 2A and A 2B receptors differs between endothelial
cells from large vessels such as umbilical vein, which express higher levels of A 2A
than A 2B , and dermal microvasculature, which preferentially express A 2B .This
appears to have profound functional implications, as A 2B AR activation strongly
induces the expression of angiogenic factors, such as interleukin-8 (IL-8), basic
fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF)
via coupling to G(q), and possibly via G12/13, instead of the classical Gs pathway
in a dermal microvascular endothelial cell line [14]. More importantly, the expres-
sion of both, A 2A and A 2B , subtypes in dermal microvascular endothelial cells is
subject to dynamic regulation by pathophysiological conditions, such as hypoxia
and cytokine exposure [12, 16, 42]. During episodes of hypoxia/ischemia, polymor-
phonuclear leukocytes are mobilized from the intravascular space to the interstitium,
and such responses may contribute significantly to tissue damage during subsequent
reperfusion. Acute increases in adenosine are important to counterbalance excessive

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