title: Chemokine receptors CXCR2 and CX3CR1 differentially regulate functional responses of bone-marrow endothelial progenitors during atherosclerotic plaque regression.
abstract: OBJECTIVE
  Atherosclerosis manifests itself as arterial plaques, which lead to heart attacks or stroke. Treatments supporting plaque regression are therefore aggressively pursued. Studies conducted in models in which hypercholesterolaemia is reversible, such as the Reversa mouse model we have employed in the current studies, will be instrumental for the development of such interventions. Using this model, we have shown that advanced atherosclerosis regression occurs when lipid lowering is used in combination with bone-marrow endothelial progenitor cell (EPC) treatment. However, it remains unclear how EPCs home to regressing plaques and how they augment atherosclerosis reversal. Here we identify molecules that support functional responses of EPCs during plaque resolution.
  
  
  RESULTS
  Chemokines CXCL1 and CX3CL1 were detected in the vascular wall of atheroregressing Reversa mice, and their cognate receptors CXCR2 and CX3CR1 were observed on adoptively transferred EPCs in circulation. We tested whether CXCL1-CXCR2 and CX3CL1-CX3CR1 axes regulate functional responses of EPCs during plaque reversal. We show that pharmacological inhibition of CXCR2 or CX3CR1, or genetic inactivation of these two chemokine receptors interfered with EPC-mediated advanced atherosclerosis regression. We also demonstrate that CXCR2 directs EPCs to regressing plaques while CX3CR1 controls a paracrine function(s) of these cells.
  
  
  CONCLUSIONS
  CXCR2 and CX3CR1 differentially regulate EPC functional responses during atheroregression. Our study improves understanding of how chemokines and chemokine receptors regulate plaque resolution, which could determine the effectiveness of interventions reducing complications of atherosclerosis.
authors.affiliation: Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
authors.forename: Oana
authors.initials: O
authors.lastname: Herlea-Pana
authors.affiliation: Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
authors.forename: Longbiao
authors.initials: L
authors.lastname: Yao
authors.affiliation: Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Heuser-Baker
authors.affiliation: Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Qiongxin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Arthritis and Clinical Immunology Programs, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Constantin
authors.initials: C
authors.lastname: Georgescu
authors.affiliation: Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
authors.affiliation: Cardiovascular Biology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA jana-barlic-dicen@omrf.org.
authors.forename: Jana
authors.initials: J
authors.lastname: Barlic-Dicen
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B
keywords: Atherosclerosis regression; Chemokine receptor CX3CR1; Chemokine receptor CXCR2; Endothelial progenitor cell