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Molecular Medicine

, Volume 20, Issue 1, pp 435–447 | Cite as

Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

  • Harold H. BachIV
  • Yee M. Wong
  • Abhishek Tripathi
  • Amanda M. Nevins
  • Richard L. Gamelli
  • Brian F. Volkman
  • Kenneth L. Byron
  • Matthias Majetschak
Research Article

Abstract

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.

Notes

Acknowledgments

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.

Supplementary material

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Authors and Affiliations

  • Harold H. BachIV
    • 1
    • 2
  • Yee M. Wong
    • 1
  • Abhishek Tripathi
    • 1
  • Amanda M. Nevins
    • 3
  • Richard L. Gamelli
    • 1
  • Brian F. Volkman
    • 3
  • Kenneth L. Byron
    • 2
  • Matthias Majetschak
    • 1
    • 2
    • 4
  1. 1.Department of SurgeryLoyola University ChicagoMaywoodUSA
  2. 2.Department of Molecular Pharmacology and TherapeuticsLoyola University ChicagoMaywoodUSA
  3. 3.Department of BiochemistryMedical College of WisconsinMilwaukeeUSA
  4. 4.Loyola University ChicagoMaywoodUSA

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