title: Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction.
abstract: BACKGROUND
  Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatory cell NADPH oxidases. The predominant source of reactive oxygen species, eg, vascular (endothelial, smooth muscle, adventitial) versus phagocytic NADPH oxidase, and the role of myelomonocytic cells in mediating arterial hypertension have not been defined yet.
  
  
  RESULTS
  Angiotensin II (1 mg · kg(-1) · d(-1) for 7 days) increased the number of both CD11b(+)Gr-1(low)F4/80(+) macrophages and CD11b(+)Gr-1(high)F4/80(-) neutrophils in mouse aorta (verified by flow cytometry). Selective ablation of lysozyme M-positive (LysM(+)) myelomonocytic cells by low-dose diphtheria toxin in mice with inducible expression of the diphtheria toxin receptor (LysM(iDTR) mice) reduced the number of monocytes in the circulation and limited ATII-induced infiltration of these cells into the vascular wall, whereas the number of neutrophils was not reduced. Depletion of LysM(+) cells attenuated ATII-induced blood pressure increase (measured by radiotelemetry) and vascular endothelial and smooth muscle dysfunction (assessed by aortic ring relaxation studies) and reduced vascular superoxide formation (measured by chemiluminescence, cytochrome c assay, and oxidative fluorescence microtopography) and the expression of NADPH oxidase subunits gp91(phox) and p67(phox) (assessed by Western blot and mRNA reverse-transcription polymerase chain reaction). Adoptive transfer of wild-type CD11b(+)Gr-1(+) monocytes into depleted LysM(iDTR) mice reestablished ATII-induced vascular dysfunction, oxidative stress, and arterial hypertension, whereas transfer of CD11b(+)Gr-1(+) neutrophils or monocytes from gp91(phox) or ATII receptor type 1 knockout mice did not. CONCLUSIONS- Infiltrating monocytes with a proinflammatory phenotype and macrophages rather than neutrophils appear to be essential for ATII-induced vascular dysfunction and arterial hypertension.
authors.affiliation: 2(nd) Medical Clinic, University Medical Center Mainz, Germany. wenzelp@uni-mainz.de
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.forename: Jan
authors.initials: J
authors.lastname: Stratmann
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Swenja
authors.initials: S
authors.lastname: Schuhmacher
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Karbach
authors.forename: Melanie
authors.initials: M
authors.lastname: Schwenk
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006973:Hypertension / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009113:Muramidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D016897:Respiratory Burst / Q000502:physiology; D014657:Vasculitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D017382:Reactive Oxygen Species; D019707:Receptors, Chemokine; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D009113:Muramidase; C472450:lysozyme M, mouse