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      EP3 Blockade Adds to the Effect of TP Deficiency in Alleviating Endothelial Dysfunction in Atherosclerotic Mouse Aortas

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          Abstract

          Endothelial dysfunction, which leads to ischemic events under atherosclerotic conditions, can be attenuated by antagonizing the thromboxane-prostanoid receptor (TP) that mediates the vasoconstrictor effect of prostanoids including prostacyclin (PGI 2). This study aimed to determine whether antagonizing the E prostanoid receptor-3 (EP3; which can also be activated by PGI 2) adds to the above effect of TP deficiency (TP –/–) under atherosclerotic conditions and if so, the underlying mechanism(s). Atherosclerosis was induced in ApoE –/– mice and those with ApoE –/– and TP –/–. Here, we show that in phenylephrine pre-contracted abdominal aortic rings with atherosclerotic lesions of ApoE –/–/TP –/– mice, although an increase of force (which was larger than that of non-atherosclerotic controls) evoked by the endothelial muscarinic agonist acetylcholine to blunt the concurrently activated relaxation in ApoE –/– counterparts was largely removed, the relaxation evoked by the agonist was still smaller than that of non-atherosclerotic TP –/– mice. EP3 antagonism not only increased the above relaxation, but also reversed the contractile response evoked by acetylcholine in NO synthase-inhibited atherosclerotic ApoE –/–/TP –/– rings into a relaxation sensitive to I prostanoid receptor antagonism. In ApoE –/– atherosclerotic vessels the expression of endothelial NO synthase was decreased, yet the production of PGI 2 (which evokes contraction via both TP and EP3) evoked by acetylcholine was unaltered compared to non-atherosclerotic conditions. These results demonstrate that EP3 blockade adds to the effect of TP –/– in uncovering the dilator action of natively produced PGI 2 to alleviate endothelial dysfunction in atherosclerotic conditions.

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          The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

          Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.
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            Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.

            Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.
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              Endothelium-derived relaxing and contracting factors.

              Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                26 September 2019
                2019
                : 10
                : 1247
                Affiliations
                [1] 1Department of Cardiology, First Affiliated Hospital, Shantou University Medical College , Shantou, China
                [2] 2Cardiovascular Research Center, Shantou University Medical College , Shantou, China
                Author notes

                Edited by: Michael A. Hill, University of Missouri, United States

                Reviewed by: Paul M. Vanhoutte, The University of Hong Kong, Hong Kong; Alister McNeish, University of Reading, United Kingdom

                *Correspondence: Bin Liu, bliu0210@ 123456yahoo.com

                These authors have contributed equally to this work

                This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2019.01247
                6775864
                31611817
                98b04b09-e63b-4688-81e2-cd6c1499c394
                Copyright © 2019 Hu, Liu, Xu, Wu, Guo, Zhang, Leng, Ge, Yu, Guo and Zhou.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 April 2019
                : 12 September 2019
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 56, Pages: 12, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31771272
                Award ID: 81970433
                Award ID: 81770678
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                pgi2,prostanoid receptors,endothelium,relaxation,contraction,atherosclerosis
                Anatomy & Physiology
                pgi2, prostanoid receptors, endothelium, relaxation, contraction, atherosclerosis

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