title: Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure.
abstract: BACKGROUND
  Hypertension caused by increased renin-angiotensin system activation is associated with elevated reactive oxygen species production. Previous studies implicate NADPH oxidase (Nox) proteins as important reactive oxygen species sources during renin-angiotensin system activation, with different Nox isoforms being potentially involved. Among these, Nox2 is expressed in multiple cell types, including endothelial cells, fibroblasts, immune cells, and microglia. Blood pressure (BP) is regulated at the central nervous system, renal, and vascular levels, but the cell-specific role of Nox2 in BP regulation is unknown.
  
  
  METHODS
  We generated a novel mouse model with a floxed Nox2 gene and used Tie2-Cre, LysM Cre, or Cdh5-CreERT2 driver lines to develop cell-specific models of Nox2 perturbation to investigate its role in BP regulation.
  
  
  RESULTS
  Unexpectedly, Nox2 deletion in myeloid but not endothelial cells resulted in a significant reduction in basal BP. Both Tie2-CreNox2 knockout (KO) mice (in which Nox2 was deficient in both endothelial cells and myeloid cells) and LysM CreNox2KO mice (in which Nox2 was deficient in myeloid cells) had significantly lower BP than littermate controls, whereas basal BP was unaltered in Cdh5-CreERT2 Nox2KO mice (in which Nox2 is deficient only in endothelial cells). The lower BP was attributable to an increased NO bioavailability that dynamically dilated resistance vessels in vivo under basal conditions without a change in renal function. Myeloid-specific Nox2 deletion had no effect on angiotensin II-induced hypertension, which, however, was blunted in Tie2-CreNox2KO mice, along with preservation of endothelium-dependent relaxation during angiotensin II stimulation.
  
  
  CONCLUSIONS
  We identify a hitherto unrecognized modulation of basal BP by myeloid cell Nox2, whereas endothelial cell Nox2 regulates angiotensin II-induced hypertension. These results identify distinct cell-specific roles for Nox2 in BP regulation.
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Can Martin
authors.initials: CM
authors.lastname: Sag
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Moritz
authors.initials: M
authors.lastname: Schnelle
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Juqian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Colin E
authors.initials: CE
authors.lastname: Murdoch
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Protti
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Celio X C
authors.initials: CXC
authors.lastname: Santos
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Greta
authors.initials: G
authors.lastname: Sawyer
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Heloise
authors.initials: H
authors.lastname: Mongue-Din
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Richards
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.).
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Eaton
authors.affiliation: From King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, United Kingdom (C.M.S., M.S., J.Z., C.E.M., A.P., C.X.C.S., G.S., X.Z., H.M.-D., D.A.R., A.C.B., A.P., P.J.E., A.M.S.); Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (C.M.S., L.S.M.); Department of Cardiology and Pneumology, Medical Center Goettingen, Germany (M.S.); and Center for Cardiology and Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany (S.K., P.W.). ajay.shah@kcl.ac.uk.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency*
chemical_list: D008562:Membrane Glycoproteins; D000804:Angiotensin II; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: NADPH oxidase; angiotensin II; blood pressure; mice