Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

Can Martin Sag; Moritz Schnelle; Juqian Zhang; Colin E Murdoch; Sabine Kossmann; Andrea Protti; Celio X C Santos; Greta J Sawyer; Xiaohong Zhang; Heloise Mongue-Din; Daniel A Richards; Alison C Brewer; Oleksandra Prysyazhna; Lars S Maier; Philip Wenzel; Philip J Eaton; Ajay M Shah

doi:10.1161/CIRCULATIONAHA.116.023877

Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

Can Martin Sag, Moritz Schnelle, Juqian Zhang, Colin E Murdoch, Sabine Kossmann, Andrea Protti, Celio X C Santos, Greta J Sawyer, Xiaohong Zhang, Heloise Mongue-Din, Daniel A Richards, Alison C Brewer, Oleksandra Prysyazhna, Lars S Maier, Philip Wenzel, Philip J Eaton, Ajay M Shah

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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.

Original language	English
Pages (from-to)	2163-2177
Journal	Circulation (Baltimore)
Volume	135
Issue number	22
Early online date	15 Mar 2017
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.116.023877
Publication status	Published - 30 May 2017

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10.1161/CIRCULATIONAHA.116.023877Licence: CC BY

Distinct Regulatory Effects of_SAG_Accepted7March2017Publishedonline15March2017_GOLD VoR (CC BY)Final published version, 1.73 MBLicence: CC BY

Cite this

Sag, C. M., Schnelle, M., Zhang, J., Murdoch, C. E., Kossmann, S., Protti, A., Santos, C. X. C., Sawyer, G. J., Zhang, X., Mongue-Din, H., Richards, D. A., Brewer, A. C., Prysyazhna, O., Maier, L. S., Wenzel, P., Eaton, P. J., & Shah, A. M. (2017). Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure. Circulation (Baltimore), 135(22), 2163-2177. https://doi.org/10.1161/CIRCULATIONAHA.116.023877

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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.",

author = "Sag, {Can Martin} and Moritz Schnelle and Juqian Zhang and Murdoch, {Colin E} and Sabine Kossmann and Andrea Protti and Santos, {Celio X C} and Sawyer, {Greta J} and Xiaohong Zhang and Heloise Mongue-Din and Richards, {Daniel A} and Brewer, {Alison C} and Oleksandra Prysyazhna and Maier, {Lars S} and Philip Wenzel and Eaton, {Philip J} and Shah, {Ajay M}",

year = "2017",

month = may,

day = "30",

doi = "10.1161/CIRCULATIONAHA.116.023877",

language = "English",

volume = "135",

pages = "2163--2177",

journal = "Circulation (Baltimore)",

issn = "0009-7322",

publisher = "American Heart Association, Inc.",

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Sag, CM , Schnelle, M, Zhang, J, Murdoch, CE, Kossmann, S, Protti, A, Santos, CXC, Sawyer, GJ , Zhang, X , Mongue-Din, H , Richards, DA , Brewer, AC , Prysyazhna, O, Maier, LS, Wenzel, P, Eaton, PJ & Shah, AM 2017, 'Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure', Circulation (Baltimore), vol. 135, no. 22, pp. 2163-2177. https://doi.org/10.1161/CIRCULATIONAHA.116.023877

TY - JOUR

T1 - Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

AU - Sag, Can Martin

AU - Schnelle, Moritz

AU - Zhang, Juqian

AU - Murdoch, Colin E

AU - Kossmann, Sabine

AU - Protti, Andrea

AU - Santos, Celio X C

AU - Sawyer, Greta J

AU - Zhang, Xiaohong

AU - Mongue-Din, Heloise

AU - Richards, Daniel A

AU - Brewer, Alison C

AU - Prysyazhna, Oleksandra

AU - Maier, Lars S

AU - Wenzel, Philip

AU - Eaton, Philip J

AU - Shah, Ajay M

PY - 2017/5/30

Y1 - 2017/5/30

N2 - 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.

AB - 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.

U2 - 10.1161/CIRCULATIONAHA.116.023877

DO - 10.1161/CIRCULATIONAHA.116.023877

M3 - Article

C2 - 28298457

SN - 0009-7322

VL - 135

SP - 2163

EP - 2177

JO - Circulation (Baltimore)

JF - Circulation (Baltimore)

IS - 22

ER -

Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

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