Uridine adenosine tetraphosphate and purinergic signaling in cardiovascular system: An update

Uridine adenosine tetraphosphate (Up ₄ A), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent endothelium-derived vasoconstrictor in perfused rat kidney. Subsequently, the effect of Up ₄ A on vascular tone regulation was intensively investigated in arteries isolated from different vascular beds in rodents including rat pulmonary arteries, aortas, mesenteric and renal arteries as well as mouse aortas, in which Up ₄ A produces vascular contraction. In contrast, Up ₄ A produces vascular relaxation in porcine coronary small arteries and rat aortas. Intravenous infusion of Up ₄ A into conscious rats or mice decreases blood pressure, and intravenous bolus injection of Up ₄ A into anesthetized mice increases coronary blood flow, indicating an overall vasodilator influence in vivo. Although Up ₄ A is the first dinucleotide described that contains both purine and pyrimidine moieties, its cardiovascular effects are exerted mainly through activation of purinergic receptors. These effects not only encompass regulation of vascular tone, but also endothelial angiogenesis, smooth muscle cell proliferation and migration, and vascular calcification. Furthermore, this review discusses a potential role for Up ₄ A in cardiovascular pathophysiology, as plasma levels of Up ₄ A are elevated in juvenile hypertensive patients and Up ₄ A-mediated vascular purinergic signaling changes in cardiovascular disease such as hypertension, diabetes, atherosclerosis and myocardial infarction. Better understanding the vascular effect of the novel dinucleotide Up ₄ A and the purinergic signaling mechanisms mediating its effects will enhance its potential as target for treatment of cardiovascular disease.