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 journalArticlepeer-review

103 Citations (Scopus)


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
Pages (from-to)1861-1871
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number8
Publication statusPublished - Aug 2013
Externally publishedYes


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