title: M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure.
abstract: Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. In the present study, we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with ANG II (0.7 mg·kg(-1)·day(-1), 14 days) had elevated systolic BP (158 ± 3 mmHg) compared with saline-treated animals (122 ± 3 mmHg). Flow cytometry revealed that ANG II infusion increased numbers of CD45(+)CD11b(+)Ly6C(hi) monocytes and CD45(+)CD11b(+)F4/80(+) macrophages by 10- and 2-fold, respectively. The majority of macrophages were positive for the M2 marker CD206 but negative for the M1 marker inducible nitric oxide synthase. Expression of other M2 genes (arginase-1, Fc receptor-like S scavenger receptor, and receptor-1) was elevated in aortas from ANG II-treated mice, whereas M1 genes [TNF and chemokine (C-X-C motif) ligand 2] were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed chemokine (C-C motif) receptor 2 (CCR2) to be upregulated in aortas from ANG II-treated mice, while flow cytometry identified Ly6C(hi) monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344; 30 mg·kg(-1)·day(-1)), 7 days after the commencement of ANG II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss, and BP in ANG II-treated mice. Thus, ANG II-dependent hypertension in mice is associated with Ly6C(hi) monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents ANG II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Antony
authors.initials: A
authors.lastname: Vinh
authors.affiliation: School of Chemistry, Monash University, Clayton, Victoria, Australia;
authors.forename: Kellie L
authors.initials: KL
authors.lastname: Tuck
authors.affiliation: School of Biomedical Sciences, Victoria University, St Albans, Victoria, Australia;
authors.forename: Samy
authors.initials: S
authors.lastname: Sakkal
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Shalini M
authors.initials: SM
authors.lastname: Krishnan
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Maggie
authors.initials: M
authors.lastname: Lieu
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Henry
authors.initials: H
authors.lastname: Diep
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia;
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria, Australia;
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia;
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
authors.affiliation: Translational Medicine Laboratory, Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Cracow, Poland; and.
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, Victoria, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, Victoria, Australia Grant.Drummond@monash.edu.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004549:Elastin / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D052247:Nitric Oxide Synthase Type II; D001119:Arginase
keywords: angiotensin II; blood pressure; chemokine (C-C motif) receptor 2; hypertension; macrophage polarization; vessel remodeling