Distinct regulatory effects of myeloid cell and endothelial cell Nox2 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 (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)
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Abstract

Background: Hypertension due to increased renin angiotensin system (RAS) activation is associated with elevated reactive oxygen species (ROS) production. Previous studies implicate NADPH oxidase (Nox) proteins as important ROS sources during RAS 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 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. Tie2-CreNox2 knockout (KO) mice (in which Nox2 was deficient in both endothelial cells and myeloid cells) and LysM Cre Nox2KO mice (in which Nox2 was deficient in myeloid cells) both had significantly lower BP than littermate controls whereas basal BP was unaltered in Cdh5-CreERT2 Nox2 KO mice (in which Nox2 is deficient only in endothelial cells). The lower BP was attributable to an increased NO bioavailability which dynamically dilated resistance vessels in vivo under basal conditions, without 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 languageEnglish
Pages (from-to)2163-2177
Number of pages15
JournalCirculation
Volume135
Issue number22
DOIs
Publication statusPublished - 15 Mar 2017

Keywords

  • angiotensin II
  • blood pressure
  • mice
  • NADPH oxidase

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