Peripheral arterial occlusive disease (PAOD) of lower extremities is becoming more prevalent worldwide. The general prognosis is particularly negative with a high prevalence of coronary heart disease and cerebrovascular disease. Diabetic foot ulcers occur in 15% of all the patients with diabetes and proceed to lower-leg amputations. In diabetic ulcers, wound healing is impaired because of delayed angiogenesis. In both pathological conditions, therapeutic angiogenesis using angiogenic growth factors, particularly Vascular Endothelial Growth Factor VEGF, is expected to be a valuable treatment. The most used approaches are based on VEGF local delivery or gene therapy, but they failed to meet the expected primary goals of therapy. Adenosine receptor stimulation can induce VEGF expression in many types of cells and this may be achieved by stimulating the A2A or A2B receptor or both, following the signalling pathways activated by hypoxia. Polideoxyribonucleotide (PDRN) is obtained from sperm trout by an extraction process. The compounds hold a mixture of deoxyribonucleotides polymers with chain lengths ranging between 50 and 2000 bp. PDRN is able to stimulate VEGF production during pathological conditions of low tissue perfusion. It likely acts through the stimulation of A2A receptors. Furthermore, acute and chronic toxicity studies showed a good safety profile. PDRN has been shown to be effective in an experimental model of PAOD, hind limb ischemia, impaired wound healing and burn injury. Preliminary studies and ongoing clinical trials predict a significant therapeutic efficacy in patients. These data lead to hypothesize a role for PDRN in therapeutic angiogenesis.