Ecto-5′-Nucleotidase, CD73, Is an Endothelium-Derived Hyperpolarizing Factor Synthase

Abstract

Objective Adenosine dilates human coronary arteries by activating potassium channels in an endothelial cell-independent manner. Cell surface ecto-5’-nucleotidase (CD73) rapidly dephosphorylates extracellular adenosine 5’-monophosphate to adenosine. We tested the hypothesis that coronary vasodilation to adenine nucleotides is mediated by an endothelial CD73-dependent, extracellular production of adenosine that acts as an endothelium-derived hyperpolarizing factor (EDHF). Methods and Results Videomicroscopy showed that adenine nucleotides but not inosine potently dilated and hyperpolarized human coronary arteries independent of NO, prostacyclin and classical EDHFs, whereas endothelial denudation, adenosine receptor antagonism, adenosine deaminase or CD73 blockers reduced vasodilations. Liquid chromatography-electrospray ionization-mass spectrometry revealed adenosine accumulation in perfusates from arteries in the presence of adenosine 5’-diphosphate. CD73 was localized on the cell surface of endothelial cells but not of vascular smooth muscle cells, and its deficiency suppressed vasodilation of mouse coronary arteries to adenine nucleotides and augmented vasodilation to adenosine. Adenosine dose-dependently dilated and hyperpolarized human coronary arteries to a similar extent as adenosine 5’-diphosphate. Conclusions Coronary vasodilation to adenine nucleotides is associated with endothelial CD73-dependent production of extracellular adenosine that acts as an EDHF by relaxing and hyperpolarizing underlying vascular smooth muscle cells via activating adenosine receptors. Thus CD73 is a novel EDHF synthase in human and mouse coronary arteries.

Endothelial function is impaired in conduit arteries of pannexin1 knockout mice

“…Extracellular ATP may induce relaxation either itself, via endothelial P2 receptors [3], or after degradation by ectonucleotidases to adenosine, a potent vascular dilator [3,27]. Our findings of the decreased endothelium-dependent relaxation and the anticontractile action of the endothelium in Panx1 −/− mice suggest the participation of Panx1 in these mechanisms.…”

The role of ecto-5′-nucleotidase in endothelial dysfunction and vascular pathologies

“…CD73 may play an important role in the regulation of the coronary circulation by generating adenosine as an endothelium-derived hyperpolarizing factor. Coronary artery dilation is mediated by an endothelial CD73-dependent production of extracellular adenosine that induces vascular smooth muscle cells hyperpolarization and relaxation through stimulation of adenosine receptors and potassium channels [33].…”

Role of Adenosine Receptor(s) in the Control of Vascular Tone in the Mouse Pudendal Artery

“…Recently, adenosine was described as an EDHF, with CD73 as an EDHF synthase, owing to its ability to relax and hyperpolarize VSMCs (Ohta et al, 2013). We looked at the effect of the genetic deletion of either A 2A AR or A 2B AR on endothelium-mediated vasorelaxation in PAs.…”

“…Intracellular adenosine levels are primarily regulated by adenosine kinase, which converts adenosine to AMP, whereas extracellular adenosine levels are critically regulated by adenosine deaminase, which degrades adenosine to inosine (Blackburn, 2003;Ham and Evans, 2012;Wen and Xia (2012)). Recently, adenosine was described as an EDHF because of its ability to relax and hyperpolarize vascular smooth muscle cells (VSMC) (Ohta et al, 2013). The activation of adenosine receptors (ARs) is implicated in the modulation of renal and cardiovascular functions, as well as erectile function, with both in vivo and in vitro studies demonstrating that, like NO, adenosine is a potent vasodilator This study was supported by the National Institutes of Health [Grants HL027339, HL094447, and U54GM104942 to S.J.M.)…”