title: Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular α₁-adrenergic receptor function.
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.
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois, United States of America.
authors.forename: Harold H
authors.initials: HH
authors.lastname: Bach
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America.
authors.forename: Yee M
authors.initials: YM
authors.lastname: Wong
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Nevins
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois, United States of America.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Byron
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois, United States of America.
authors.forename: Matthias
authors.initials: M
authors.lastname: Majetschak
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12 / Q000494:pharmacology; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011917:Rats, Inbred Lew; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D054387:Receptors, CXCR / Q000819:agonists / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012771:Shock, Hemorrhagic / Q000503:physiopathology; D025801:Ubiquitin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C501898:Ackr3 protein, rat; D000322:Adrenergic Agonists; D001596:Benzylamines; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008024:Ligands; D009842:Oligopeptides; D018340:Receptors, Adrenergic, alpha-1; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; C504129:TC14012; D025801:Ubiquitin; D010656:Phenylephrine; C088327:plerixafor