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

Abstract

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 *

Synthetic Strategies for Dinucleotides Synthesis

“…In particular, they interact with the P2YRs, a family of high therapeutic relevance [2,23,29,30]. The P2Y 1 , P2Y 11 , P2Y 12 , and P2Y 13 receptors are activated by adenosine 5 -di-or triphosphates (ADP and ATP), while uracil nucleotides (UDP and UTP) are the endogenous agonists for the P2Y 4 , P2Y 6 , and P2Y 14 receptors. On the other hand, the P2Y 2 receptor responds to both ATP and UTP.…”

“…The authors assumed that this dinucleotide could have a role in cellular communication as a "signal nucleotide". Later, Up 4 A was the first endogenous dinucleotide, possessing both purine and pyrimidine moieties, to be identified in living organisms [5,6]. Currently, 17 symmetrical or mixed Np n Ns have been isolated from human tissues and characterized [2].…”

A 15-Year Study on Up4A in Cardiovascular Disease

“…During the following years, the research was focused on the vascular effect of Up 4 A in different vascular beds of various species. This mainly includes the acute effect of Up 4 A on vascular function in both health and various cardiovascular diseases including hypertension, atherosclerosis, myocardial infarction, and diabetes, and the trophic effect of Up 4 A on vascular proliferation, migration, angiogenesis, and calcification (Matsumoto et al, 2015;Zhou et al, 2019). Up 4 A exerts biological effects by activating purinergic receptors (PRs) to regulate cardiovascular (dys)function.…”

“…At least seven P2XRs, and eight P2YRs have been identified to date (Burnstock, 2017). In the vasculature, activation of A1R and A3R can induce contraction, whereas activation of A 2A R and A 2B R typically produce vascular relaxation (Zhou et al, 2019). In contrast to P1Rs, the effects of the activation of P2R subtypes may be tissue-and cell-dependent.…”

“…In contrast to P1Rs, the effects of the activation of P2R subtypes may be tissue-and cell-dependent. In general, activation of P2R subtypes in endothelial cells are thought to induce vasodilation, while activation of P2Rs in smooth muscle cells can induce vasoconstriction (Zhou et al, 2019). Of note, the pharmacological action of Up 4 A on vascular function and the Up 4 A-mediated purinergic signaling have been shown to be altered in cardiovascular disease (Zhou et al, 2019).…”