Circulating Blood Endothelial Nitric Oxide Synthase Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 33; no. 8; pp. 1861 - 1871
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.08.2013
• Subjects: Animals; Arginine - blood; Arginine - pharmacokinetics; Blood Pressure - physiology; Carbon Radioisotopes; Citrulline - blood; Citrulline - pharmacokinetics; Endothelium, Vascular - enzymology; Enzyme Inhibitors - pharmacology; Erythrocytes - enzymology; Homeostasis - physiology; Hypertension - genetics; Hypertension - metabolism; Mice; Mice, Knockout; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - blood; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Nitrites - blood; Signal Transduction - physiology; blood pressure; bone marrow transplant; nitric oxide synthase; blood
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.112.301068

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 C-arginine into 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.