Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular alpha(1)-adrenergic receptor function Journal Article

Local Library Link: Find It @ Loyola

Authors: Bach, H. H., 4th; Wong, Y. M.; Tripathi, A; Nevins, A. M.; Gamelli, R. L.; Volkman, B. F.; Byron, K. L.; Majetschak, M
Article Title: Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular alpha(1)-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 alpha1-adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced alpha1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized alpha1-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 alpha1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate alpha1-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.
Journal Title: Molecular medicine (Cambridge, Mass.)
Volume: 20
ISSN: 1528-3658; 1076-1551
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: 435
End Page: 447
Language: eng
DOI/URL:

10.2119/molmed.2014.00101
Notes: GR: T32GM008750/GM/NIGMS NIH HHS/United States; JID: 9501023; OID: NLM: PMC4212013; 2014/05/09 [received]; 2014/07/14 [accepted]; 2014/07/14 [aheadofprint]; epublish