Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis

Katherine C. Wood, Miriam M. Cortese-Krott, Jason C. Kovacic, Audrey Noguchi, Virginia B. Liu, Xunde Wang, Nalini Raghavachari, Manfred Boehm, Gregory J. Kato, Malte Kelm, Mark T. Gladwin

Research output: Contribution to journalArticle

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. APPROACH AND 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 14C-arginine into 14C-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.

Original languageEnglish (US)
Pages (from-to)1861-1871
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number8
DOIs
StatePublished - Aug 2013
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type III
Nitrites
Blood Cells
Nitric Oxide
Homeostasis
Blood Pressure
Blood Vessels
Arginine
Erythrocytes
Citrulline
NG-Nitroarginine Methyl Ester
Endothelium
Proteins
Leukocytes
Blood Platelets
Transplants

Keywords

  • Blood
  • Blood pressure
  • Bone marrow transplant
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. / Wood, Katherine C.; Cortese-Krott, Miriam M.; Kovacic, Jason C.; Noguchi, Audrey; Liu, Virginia B.; Wang, Xunde; Raghavachari, Nalini; Boehm, Manfred; Kato, Gregory J.; Kelm, Malte; Gladwin, Mark T.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 33, No. 8, 08.2013, p. 1861-1871.

Research output: Contribution to journalArticle

Wood, KC, Cortese-Krott, MM, Kovacic, JC, Noguchi, A, Liu, VB, Wang, X, Raghavachari, N, Boehm, M, Kato, GJ, Kelm, M & Gladwin, MT 2013, 'Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 8, pp. 1861-1871. https://doi.org/10.1161/ATVBAHA.112.301068
Wood, Katherine C. ; Cortese-Krott, Miriam M. ; Kovacic, Jason C. ; Noguchi, Audrey ; Liu, Virginia B. ; Wang, Xunde ; Raghavachari, Nalini ; Boehm, Manfred ; Kato, Gregory J. ; Kelm, Malte ; Gladwin, Mark T. / Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2013 ; Vol. 33, No. 8. pp. 1861-1871.
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AU - Cortese-Krott, Miriam M.

AU - Kovacic, Jason C.

AU - Noguchi, Audrey

AU - Liu, Virginia B.

AU - Wang, Xunde

AU - Raghavachari, Nalini

AU - Boehm, Manfred

AU - Kato, Gregory J.

AU - Kelm, Malte

AU - Gladwin, Mark T.

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N2 - 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. APPROACH AND 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 14C-arginine into 14C-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.

AB - 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. APPROACH AND 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 14C-arginine into 14C-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.

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