Stimulation of Wound Revascularization by Adenosine Receptor Activation - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 104

wild type, tPA deficient and uPA deficient mice, and the effect of adenosine A 2A
receptor activation on the production and secretion of t-PA, u-PA, and PAI-1 by
dermal microvascular endothelial cells and the monocytic cell line THP-1 [60, 61].
Annexin II is a proposed endothelial cell co-receptor for plasminogen and t-PA [20]
and in vitro studies have suggested that this endothelial cell surface protein can
stimulate t-PA-mediated plasminogen activation in the complete absence of fibrin
[31]. We have found that promotion of wound healing by topical application of
a selective adenosine A 2A receptor agonist requires the expression of tissue (tPA)
but not urokinase plasminogen activator (uPA). Our preliminary results in human
dermal microvascular endothelial cells point to a new hypothesis, that tPA partic-
ipates of the proangiogenic effect of A 2A receptor activation through a complex
mechanism that involves its main inhibitor PAI-1 and its cell receptor annexin II
(Fig. 6.7).
Fig. 6.7 Proposed mechanism for adenosine A 2A receptor stimulation of plasmin generation on
the surface of endothelial cells and its implication in angiogenesis. Adenosine A2A receptor acti-
vation in endothelial cells diminishes the release of the plasminogen activator inhibitor-1 (PAI-1)
and promotes the production of annexin II, which acts as a co-receptor for plasminogen and its
activator tPA
6.6 Conclusion
Adenosine, through interaction with specific membrane receptors, promotes the for-
mation of new vessels by increasing both local vessel sprouting and recruitment
of endothelial progenitor cells from the bone marrow. The contribution of the dif-
ferent receptor subtypes to the angiogenic effect of adenosine depends mainly on
the pathophysiological conditions of the organ affected. While endothelial cell A 2B
receptor activation appears to prevail in revascularization of hypoxic tissue and in
retinopathy, A 2A receptors play a relevant role in physiological revascularization of
damaged tissues. In addition, all the adenosine receptors subtypes expressed by res-
ident and migrating cells modulate the release of regulatory molecules that provide
a proper environment for neovascularization.