Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function
Chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor (ACKR) 3 ligands have been reported to modulate cardiovascular function in various disease models. The underlying mechanisms, however, remain unknown. Thus, it was the aim of the present study to determine how pharmacological modulation of CXCR4 and ACKR3 regulate cardiovascular function. In vivo administration of TC14012, a CXCR4 antagonist and ACKR3 agonist, caused cardiovascular collapse in normal animals. During the cardiovascular stress response to hemorrhagic shock, ubiquitin, a CXCR4 agonist, stabilized blood pressure, whereas coactivation of CXCR4 and ACKR3 with CXC chemokine ligand 12 (CXCL12), or blockade of CXCR4 with AMD3100 showed opposite effects. While CXCR4 and ACKR3 ligands did not affect myocardial function, they selectively altered vascular reactivity upon α1-adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced α1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized α1-AR-mediated vasoconstriction. The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically. CXCR4 and ACKR3 ligands did not affect vasoconstriction upon activation of voltage-operated Ca2+ channels or endothelin receptors. Effects of CXCR4 and ACKR3 agonists on vascular α1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate α1-AR reactivity in vascular smooth muscle and regulate hemodynamics in normal and pathological conditions. Our observations point toward CXCR4 and ACKR3 as new pharmacological targets to control vasore-activity and blood pressure.
The authors thank Heather M La Porte for technical help and P de Tombe, X Ji, S Sadayappan, and R. Tiniakov, Loyola University Chicago, for help with myocardial function analyses. This research was made possible, in part, by a grant that was awarded and administered by the U.S. Army Medical Research & Materiel Command (USAMRMC) and the Telemedicine and Advanced Technology Research Center (TATRC), at Fort Detrick, MD, USA, under contract number W81XWH1020122. The views, opinions and/or findings contained in this research are those of the author(s) and do not necessarily reflect the views of the Department of Defense and should not be construed as an official DoD/Army position, policy or decision unless so designated by other documentation. No official endorsement should be made. This research was also supported, in part, by grants from the American Heart Association (13GRNT17230072), the NIH (T32GM008750) and the Dr. Ralph and Marian Falk Medical Research Trust.
- 21.Bach Iv HH, Saini V, Baker TA, Tripathi A, Gamelli RL, Majetschak M. (2012) Initial assessment of the role of CXC chemokine receptor 4 after polytrauma. Mol. Med. 18:1056–66.Google Scholar
- 31.(1985) Bacterial endotoxins/pyrogens [Internet]. Silver Spring (MD): FDA; [cited 2014 Aug 29]. (Inspection technical guide). Available from: https://doi.org/www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnicalGuides/ucm072918.htm (web page last updated 2009 Feb 17).
- 32.Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press.Google Scholar
- 35.Brueggemann LI, Mani BK, Haick J, Byron KL. (2012) Exploring arterial smooth muscle Kv7 potassium channel function using patch clamp electrophysiology and pressure myography. J. Vis. Exp. 14:e4263.Google Scholar
- 55.Widney DP, Xia YR, Lusis AJ, Smith JB. (2000) The murine chemokine CXCL11 (IFN-inducible T cell alpha chemoattractant) is an IFN-gamma- and lipopolysaccharide-inducible glucocortioid-attenuated response gene expressed in lung and other tissues during endotoxemia. J. Immunol. 164:6322–31.CrossRefPubMedGoogle Scholar
- 64.Milligan G, Canals M, Pediani JD, Ellis J, Lopez-Gimenez JF. (2006) The role of GPCR dimerisation/oligomerisation in receptor signalling. Ernst Schering Found. Symp. Proc. 2:145–61.Google Scholar
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.
The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)