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

Uridine adenosine tetraphosphate (Up₄A), 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 Up₄A 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 Up₄A produces vascular contraction. In contrast, Up₄A produces vascular relaxation in porcine coronary small arteries and rat aortas. Intravenous infusion of Up₄A into conscious rats or mice decreases blood pressure, and intravenous bolus injection of Up₄A into anesthetized mice increases coronary blood flow, indicating an overall vasodilator influence in vivo. Although Up₄A 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 Up₄A in cardiovascular pathophysiology, as plasma levels of Up₄A are elevated in juvenile hypertensive patients and Up₄A-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 Up₄A and the purinergic signaling mechanisms mediating its effects will enhance its potential as target for treatment of cardiovascular disease.