Purinergic and Pyriminergic Activation of the Endothelium in Regulation of Tissue Perfusion - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 4

Fig. 1.2 Regulation of tissue perfusion. Hypoxia, metabolic acidosis and increased CO 2 cause
release of intraluminal ATP from red blood cells (RBC) and endothelial cells (EC). ATP activates
P2-receptors on endothelial cells and induces dilatation via NO and EDHF. This result in both
a local dilatation and a retrograde spreading dilatation giving a conducted response resulting in
increased blood flow to the tissue. The retrograde spreading dilation is important since the most
pronounced hypoxia, metabolic acidosis and increase in CO 2 is found on the venular side
substantially and could have major circulatory effects. A negative feedback system
may therefore be of great physiological importance to mitigate ATP release.
1.4 Role of Ectonucleotidases in Regulation of Tissue Perfusion
Extracellular ATP in the circulation is rapidly degraded into ADP, AMP and
adenosine by ectonucleotidases. Vascular NTPDase1 (CD39) is an endothelial cell
membrane protein with both ecto-ATPase and ecto-ADPase activities [38, 83].
Ectonucleotidases are released by shear stress from endothelial cells [81], and from
sympathetic nerves together with its substrate ATP, as a termination mechanism for
the signalling [66]. In exercising humans when skeletal muscle blood flow increases,
ectonucleotidases are released and it may be speculated that this could contribute to
the benefits of physical activity [82].
The importance of ectonucleotidases for tissue perfusion has been established in
several other pathophysiological situations. Endothelial ADPase activity is lost fol-
lowing ischemia-reperfusion injury, xenograft rejection and inflammation resulting
in increased levels of ATP and ADP [38, 54]. This can cause platelet aggrega-
tion and microvascular obstruction. Infusion of systemic apyrase inhibits platelet
aggregation and prolongs xenograft survival [40]. This has also been shown with
adenoviral transfer of NTPDase1 [36]. NTPDase1 is also lost in vascular cardiac
grafts subjected to oxidant stress.