Stimulation of Wound Revascularization by Adenosine Receptor Activation - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 92

events is impaired in chronic wounds, including those due to diabetes. Loss of auto-
nomic function and small fiber neuropathy is a characteristic feature of diabetic
patients and can result in impaired neurogenic control of local microcirculatory
blood flow and fluid homeostasis, diminished energy metabolism, oxygen delivery,
and inflammatory responses. These altered processes could render diabetic patients
more susceptible to tissue damage and infection [51]. Although many different
interventions have been proposed to accelerate the healing process, very few have
translated into positive clinical experience, and research is ongoing to provide better
therapeutic alternatives to promote impaired wound healing.
The metabolic messenger adenosine is an endogenous regulator of inflamma-
tion that is generated as a result of ATP catabolism in ischemic or inflamed tissues.
Adenosine mediates a wide variety of physiological effects through the activa-
tion of cell-surface receptors of which there are four subtypes, A 1 ,A 2A ,A 2B and
A 3 , all of which belong to the superfamily of seven transmembrane-spanning G-
protein coupled receptors [17, 22, 26]. All cell subtypes involved in wound healing,
macrophages, epidermal cells, fibroblasts and microvascular endothelial cells, dif-
ferentially express functional adenosine receptors, although the receptor expression
patterns vary between cellular types. Adenosine A 2A and A 2B receptors, in partic-
ular, are expressed on all cell types involved in wound healing, while A 1 and A 3
receptors were not found in microvascular endothelial cells [6, 7, 14, 27]. Several
studies indicate that adenosine agonists promote healing of cutaneous wounds
through activation of surface receptors (reviewed in [62]). We and others have
shown that selective agonists of the A 2A receptor subtype of adenosine promote
tissue repair in mice, both healthy and with impaired healing, and one such agonist,
Sonedenoson, is currently being evaluated as a prospective new therapy of dia-
betic foot ulcers. The examination of the mechanisms underlying this phenomenon
showed that adenosine facilitates the formation of the granulation tissue and the
blood vessels network that nourishes it [37, 38, 43, 63].
New vessel formation in the adult is the result of subtle and often complex
interactions between regulatory and effector molecules and occurs through the coop-
eration of two distinct mechanisms: angiogenesis, the sprouting or partitioning of
already existing vessels; and vasculogenesis, the differentiation and assembly of cir-
culating bone marrow-derived endothelial cell precursors (angioblasts) [4]. During
the sprouting phase, endothelial cells become activated and coordinately involved
in the processes of proliferation, migration, and tube formation. Once a provi-
sional vessel network is formed, the phase of resolution takes place by cessation
of endothelial cell proliferation and migration, followed by recruitment and dif-
ferentiation of smooth muscle cells and pericytes providing full functionality to the
vessel [41]. This multistep process is tightly regulated by soluble growth factors and
inhibitors, and a close interaction between adhesive extracellular matrix proteins and
their integrin receptors.
Several vasoactive metabolites produced during tissue hypoxia have been
implicated in the angiogenesis process [10]. Adenosine is also a vasodilating
metabolite whose extracellular concentration dramatically increases in injured and
oxygen deprived sites as consequence of ATP catabolism [52]. In addition, the