Stimulation of Wound Revascularization by Adenosine Receptor Activation - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 103

and they express all four adenosine receptors and the enzyme ecto-5 nucleoti-
dase (CD73) that catalyzes the extracellular conversion of AMP to adenosine [25].
Mesenchymal stem cells isolated from bone marrow of either A 2A deficient or
ecto-5 nucleotidase (CD73)-deficient mice formed significantly fewer colonies,
and this effect was mimic by culture with the adenosine A 2A receptor antagonist
ZM241385, although culture of wild type cells with the A 2A agonist CGS21680
did not enhance colony formation. Interestingly, there was a significant decrease in
CD73 expression in cells from A 2A receptor deficient mice and a marked reduction
in A 2A receptor expression in CD73 deficient mice, confirming a reciprocal regula-
tionofCD73byA 2A receptors and vice versa. Moreover, adenosine A 2A receptors
regulate the expression of differentiation antigens on the mesenchymal stem cells,
such as CD90, CD105, and procollagen alpha2 type I.
These findings indicate that adenosine via A 2A receptor plays a critical role in
promoting the proliferation and differentiation of mouse bone marrow mesenchymal
stem cell [25].
A recent study also demonstrates a role of adenosine in vasculogenesis of the
myocardium, although in this territory the adenosine receptors involved appear to
differ. Stimulation of adenosine receptors increased the adhesion of murine embry-
onic endothelial progenitor cells to cardiac endothelial cells rapidly, within minutes.
Furthermore, adenosine increased cell retention in isolated mouse hearts perfused
with embryonic endothelial precursor cells. Similarly, adhesion of human adult
culture-expanded endothelial progenitor cells to human cardiac endothelial cells
was increased by stimulation of adenosine receptors. These investigators showed
that murine embryonic endothelial precursor cells preferentially express functional
A 1 adenosine receptors, while the A 2B receptor subtype is preferentially expressed
by cardiac endothelial cells, and both subtypes are involved in the regulation of pro-
genitor cell adhesion to the endothelium by the interaction between P-selectin and
its ligand [48].
6.5 Contribution of the Fibrinolytic System to the Angiogenic
Effect of Adenosine
Besides of degrading the fibrin clot, the fibrinolytic system is an essential constituent
of the proteolytic machinery involved in the breakdown of extracellular matrix,
which enables migration of fibroblasts and endothelial cells at sites of injury. The
serine proteases urokinase (uPA) and tissue (tPA) plasminogen activators degrade
plasminogen to plasmin, which in turn degrades components of the wound matrix,
fibrinogen and fibrin, and activate several matrix metalloproteinases. Plasminogen
activation is tightly regulated by the balance between plasminogen activators tPA
and uPA and their principal inhibitors, plasminogen activator inhibitor-1 (PAI-1)
and PAI-2 [30, 50]. Since adenosine receptor agonists increase plasminogen acti-
vator release from rabbit alveolar macrophages [21], we are currently studying
the effect of a selective adenosine A 2A receptor agonist on wound closure in