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Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular α₁-adrenergic receptor function. Mol Med 2014 Oct 13;20:435-47

Date

07/18/2014

Pubmed ID

25032954

Pubmed Central ID

PMC4212013

DOI

10.2119/molmed.2014.00101

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 Ca(2+) 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 vasoreactivity and blood pressure.

Author List

Bach HH 4th, Wong YM, Tripathi A, Nevins AM, Gamelli RL, Volkman BF, Byron KL, Majetschak M

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adrenergic Agonists
Animals
Blood Pressure
Chemokine CXCL12
Heterocyclic Compounds
In Vitro Techniques
Ligands
Male
Mesenteric Arteries
Myocytes, Cardiac
Oligopeptides
Phenylephrine
Rats, Inbred Lew
Receptors, Adrenergic, alpha-1
Receptors, CXCR
Receptors, CXCR4
Shock, Hemorrhagic
Ubiquitin
Vasoconstriction
Ventricular Function, Left
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