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      Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats

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          Abstract

          Nearly all physiological processes are controlled at some level by G-protein-coupled receptor (GPCR) signaling activity. The thromboxane A2 (TXA2) receptor (TP) is a member of the GPCR family. The ultimate effect of TP receptor activation depends on the availability of specific G proteins, which in turn depend on the cell type, tissue, and disease state. However, the roles of the TXA2-TP signaling pathway executed under disease states are poorly defined. In this study, 16-week-spontaneously hypertensive rats (SHR), the 18-month-SHR (OldSHR), and the age-matched Wistar-Kyoto (WKY) rats were used to study the vasoconstriction of mesenteric resistance artery induced by TP-specific agonist, U-46619. Vasoconstriction induced by U-46619 was significantly attenuated in OldWKY and OldSHR rats, and mesenteric arteries with impaired response to U-46619 responded strongly to the adrenergic receptor agonist, phenylephrine. Similar vascular responses to U-46619 were obtained in endothelium-denuded mesenteric arteries. Accordingly, the expression of TP membrane proteins in mesenteric vessels was decreased, and the endogenous TP competitor, 8, 9-EET, in serum was increased, which was partly responsible for the decreased vascular reactivity of U-46619. Decreased TP membrane expression was associated with TP endocytosis, which involved actin cytoskeletal remodeling, including increased ratio of F-actin/G-actin in OldWKY and OldSHR rats. Hence, we studied the effects of TXA2 and its receptors on blood vessels and found that the TXA2-TP prostaglandin signaling pathway was impaired in older adults, which would facilitate the creation of “precision therapeutics” that possess selective efficacy in diseases.

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          Most cited references39

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          Regulation of receptor trafficking by GRKs and arrestins.

          To ensure that extracellular stimuli are translated into intracellular signals of appropriate magnitude and specificity, most signaling cascades are tightly regulated. One of the major mechanisms involved in the regulation of G protein-coupled receptors (GPCRs) involves their endocytic trafficking. GPCR endocytic trafficking entails the targeting of receptors to discrete endocytic sites at the plasma membrane, followed by receptor internalization and intracellular sorting. This regulates the level of cell surface receptors, the sorting of receptors to degradative or recycling pathways, and in some cases the specific signaling pathways. In this chapter we discuss the mechanisms that regulate receptor endocytic trafficking, emphasizing the role of GPCR kinases (GRKs) and arrestins in this process.
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            Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides.

            An unstable [t1/2 at 37 degrees = 32 +/- 2 (SD) sec] intermediate, thromboxane A2, was detected in the conversion of prostaglandin G2 into 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid (thromboxane B2) in platelets. The intermediate was trapped by addition of methanol, ethanol, or sodium azide to suspensions of washed human platelets incubated for 30 sec with arachidonic acid or prostaglandin G2. The structures of the resulting derivatives demonstrated that the intermediate possessed an oxane ring as in thromboxane B2 but lacked its hemiacetal hydroxyl group. Additional experiments using 18O2 or [2H8]arachidonic acid in the formation of thromboxane B2 and CH3O2H for the trapping of thromboxane A2, together with information on the t1/2 of the intermediate, indicated the presence of an oxetane structure in thromboxane A2. Incubation of arachidonic acid or prostaglandin G2 with washed platelets led to formation of an unstable factor that induced irreversible platelet aggregation and caused release of [14C]serotonin from platelets that had been incubated with [14C]serotonin. The properties and the mode of formation of this factor indicated that it was identical with thromboxane A2. Furthermore, evidence is presented that the more unstable and major component of rabbit aorta contracting substance (RCS) formed in platelets and guinea pig lung is also thromboxane A2.
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              The structural basis of arrestin-mediated regulation of G-protein-coupled receptors.

              The 4 mammalian arrestins serve as almost universal regulators of the largest known family of signaling proteins, G-protein-coupled receptors (GPCRs). Arrestins terminate receptor interactions with G proteins, redirect the signaling to a variety of alternative pathways, and orchestrate receptor internalization and subsequent intracellular trafficking. The elucidation of the structural basis and fine molecular mechanisms of the arrestin-receptor interaction paved the way to the targeted manipulation of this interaction from both sides to produce very stable or extremely transient complexes that helped to understand the regulation of many biologically important processes initiated by active GPCRs. The elucidation of the structural basis of arrestin interactions with numerous non-receptor-binding partners is long overdue. It will allow the construction of fully functional arrestins in which the ability to interact with individual partners is specifically disrupted or enhanced by targeted mutagenesis. These "custom-designed" arrestin mutants will be valuable tools in defining the role of various interactions in the intricate interplay of multiple signaling pathways in the living cell. The identification of arrestin-binding sites for various signaling molecules will also set the stage for designing molecular tools for therapeutic intervention that may prove useful in numerous disorders associated with congenital or acquired disregulation of GPCR signaling.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                12 October 2022
                2022
                : 13
                : 1019511
                Affiliations
                Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province , Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease , Institute of Cardiovascular Research , Southwest Medical University , Luzhou, Sichuan, China
                Author notes

                Edited by: Chrishan S. Samuel, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia

                Reviewed by: Katsuya Hirano, Kagawa University, Japan

                Aling Shen, Fujian University of Traditional Chinese Medicine, China

                *Correspondence: Yan Yang, wyangyan@ 123456swmu.edu.cn

                These authors have contributed equally to this work and share first authorship

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                1019511
                10.3389/fphar.2022.1019511
                9602936
                36313372
                25dc3860-3a6f-48ee-9abe-44a8651f6400
                Copyright © 2022 Zhang, Li, He, Cui, Li, Ma, Cheng, Wen, Li and Yang.

                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
                : 15 August 2022
                : 30 September 2022
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                aging-related vascular remodeling,mesenteric artery,u-46619,vasoconstriction,txa2-tp prostaglandin signaling pathway

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