title: Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis.
abstract: OBJECTIVE
  Mice genetically deficient in endothelial nitric oxide synthase (eNOS(-/-)) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. Although the current paradigm holds that this bioactivity derives specifically from the expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed.
  
  
  RESULTS
  To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted wild-type and eNOS(-/-) mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NG-nitroarginine methyl ester and repristinated by the NOS substrate L-arginine and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert (14)C-arginine into (14)C-citrulline in NOS-dependent fashion.
  
  
  CONCLUSIONS
  These are the first studies to definitively establish a role for a blood-borne eNOS, using cross-transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Wood
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Cortese-Krott
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.forename: Audrey
authors.initials: A
authors.lastname: Noguchi
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Liu
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000818:Animals; D001120:Arginine / Q000097:blood / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000502:physiology*; D002250:Carbon Radioisotopes; D002956:Citrulline / Q000097:blood / Q000493:pharmacokinetics; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D006706:Homeostasis / Q000502:physiology*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D009573:Nitrites / Q000097:blood*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D009573:Nitrites; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester
keywords: blood; blood pressure; bone marrow transplant; nitric oxide synthase