Physiological role of adenosine and its receptors in tissue hypoxia-induced

It is well known that the metabolic factors play an important role in the regulation of angiogenesis. Increased metabolic activity leads to decreased oxygen levels and causes tissue hypoxia. Hypoxia starts different signals to stimulate angiogenesis and promotes oxygen delivery to tissues. It has been suggested that released adenosine from hypoxic tissues plays a vital role in angiogenesis. In this context, the following feedback control hypothesis is proposed: Under hypoxic conditions, membrane 5´-nucleotidase dephosphorylates AMP to adenosine in the extracellular space of a cardiomyocyte, hepatocyte or other parenchymal cells. Extracellular adenosine binds and stimulates adenosine receptor that leads to the release of vascular endothelial growth factor (VEGF) from the parenchymal cell. Binding of VEGF to its receptor on the surface of endothelial cells activates proliferation and migration of these cells. Adenosine can also activate the proliferation of vascular endothelial cells through mediating other anti and proangiogenic growth factors. Adenosine can also induce vasodilation and play a role in the vascular growth and remodeling. After establishment of a new capillary network, adenosine, VEGF and other pro and antiangiogenic growth factors return to near basal concentrations, and then the angiogenesis process terminates. In some conditions up to 50–70% of the hypoxia-induced angiogenesis mediates through adenosine. Hence, the main aim of this review is to focus on the physiological role of adenosine and its receptors in the induction of angiogenesis under hypoxic conditions