NOS, NO, and the Red Cell

Cortese‐Krott, Miriam M.; Kramer, Christian M.; Kelm, Malte

doi:10.1016/b978-0-12-804273-1.00014-4

Cited by 5 publications

(9 citation statements)

References 109 publications

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“… 9 The functional significance of eNOS in RBCs has been a matter of intense debate for some time. 10 , 11 , 14 , 32 , 33 …”

Section: Discussionmentioning

confidence: 99%

“…35–39 In the bloodstream, RBCs are located closer to the endothelium downstream in the circulation, whereas, in the large elastic conduit arteries, RBCs are aligned mainly in the central bloodstream far away from the endothelial lining, thus limiting NO scavenging upstream and allowing the release of NO bioactivity downstream. 14,16…”

Section: Discussionmentioning

confidence: 99%

“…Our findings underscore unequivocally that an l-arginase-eNOS signaling cascade is effectively expressed in ECs and RBCs and, comparing the phenotype of the 4 mice lines presented here, it becomes clear that, depending on its localization, this pathway exerts distinct and complementary physi- ological effects on NO metabolism and BP control. This may be because of the specific (sub)compartmentalization of eNOS within the vessel wall and its cellular components, [35][36][37][38] the unique anatomy and function of the vascular tree 39 and its relationship with the circulating blood cells, 14 and the different half-life and distribution kinetics of the NO metabolites within the blood and the tissues. 9,16,24,[40][41][42] The functional differences of the pathway in RBCs or the vasculature may become prominent under specific pathophysiological conditions such as endothelial dysfunction or blood disorders.…”

Section: Articlementioning

confidence: 99%

“…[35][36][37][38][39] In the bloodstream, RBCs are located closer to the endothelium downstream in the circulation, whereas, in the large elastic conduit arteries, RBCs are aligned mainly in the central bloodstream far away from the endothelial lining, thus limiting NO scavenging upstream and allowing the release of NO bioactivity downstream. 14,16 In the vessel wall, eNOS is found both at the luminal side of ECs (apical EC) and the basal side of ECs. Endothelial NO is released abluminally from ECs toward the vascular smooth muscle, and, to a lesser extent, as a spillover into the blood at its luminal site.…”

Section: Articlementioning

confidence: 99%

“…8,9 The functional significance of eNOS in RBC physiology, systemic NO metabolism, and tissue protection remains controversial. [10][11][12][13][14][15][16] There are indications that eNOS in the blood may participate in the regulation of circulating nitrite levels and blood pressure (BP) homeostasis, 9 but its specific contribution is unknown. One way to test the physiological effect directly would be through genetic manipulation of eNOS in ECs versus RBCs.…”

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confidence: 99%

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Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

et al. 2021

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Background: Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) via endothelial nitric oxide synthase (eNOS) in the vessel wall is the primary regulator of blood flow and blood pressure. However, red blood cells (RBCs) also carry a catalytically active eNOS, but its role is controversial and remains undefined. This study aimed to elucidate the functional significance of red cell eNOS compared to EC eNOS for vascular hemodynamics and NO metabolism. Methods: We generated tissue-specific "loss-" and "gain-of-function" models for eNOS by using cell-specific Cre-induced gene inactivation or reactivation. We created two founder lines carrying a floxed eNOS (eNOS flox/flox ) for Cre-inducible knock out (KO), as well as gene construct with an inactivated floxed/inverted exon (eNOS inv/inv ) for a Cre-inducible knock in (KI), which respectively allow targeted deletion or reactivation of eNOS in erythroid cells (RBC eNOS KO or RBC eNOS KI mice) or endothelial cells (EC eNOS KO or EC eNOS KI mice). Vascular function, hemodynamics, and NO metabolism were compared ex vivo and in vivo . Results: The EC eNOS KOs exhibited significantly impaired aortic dilatory responses to acetylcholine, loss of flow-mediated dilation (FMD), and increased systolic and diastolic blood pressure. RBC eNOS KO mice showed no alterations in acetylcholine-mediated dilation or FMD but were hypertensive. Treatment with the NOS inhibitor L-NAME further increased blood pressure in RBC eNOS KOs, demonstrating that eNOS in both ECs and RBCs contributes to blood pressure regulation. While both EC eNOS KOs and RBC eNOS KOs had lower plasma nitrite and nitrate concentrations, the levels of bound NO in RBCs were lower in RBC eNOS KOs as compared to EC eNOS KOs. Crucially, reactivation of eNOS in ECs or RBCs rescues the hypertensive phenotype of the eNOS inv/inv mice, while the levels of bound NO were restored only in RBC eNOS KI mice. Conclusions: These data reveal that eNOS in ECs and RBCs contribute independently to blood pressure homeostasis.

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“… 9 The functional significance of eNOS in RBCs has been a matter of intense debate for some time. 10 , 11 , 14 , 32 , 33 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Articlementioning

confidence: 99%

Section: Articlementioning

confidence: 99%

mentioning

confidence: 99%

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Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

et al. 2021

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Red Blood Cells as a “Central Hub” for Sulfide Bioactivity: Scavenging, Metabolism, Transport, and Cross-Talk with Nitric Oxide

Cortese‐Krott

2020

Antioxidants & Redox Signaling

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The role of globins in cardiovascular physiology

Keller

Lechauve

Keller

et al. 2022

Physiological Reviews

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Globin proteins exist in every cell type of the vasculature, from erythrocytes to endothelial cells, vascular smooth muscle cells, and peripheral nerve cells. Many globin subtypes are also expressed in muscle tissues (including cardiac and skeletal muscle), in other organ-specific cell types, and in cells of the central nervous system. The ability of each of these globins to interact with molecular oxygen (O2) and nitric oxide (NO) is preserved across these contexts. Endothelial α-globin is an example of extra-erythrocytic globin expression. Other globins, including myoglobin, cytoglobin, and neuroglobin are observed in other vascular tissues. Myoglobin is observed primarily in skeletal muscle and smooth muscle cells surrounding the aorta or other large arteries. Cytoglobin is found in vascular smooth muscle but can also be expressed in non-vascular cell types, especially in oxidative stress conditions after ischemic insult. Neuroglobin was first observed in neuronal cells, and its expression appears to be restricted mainly to the central and peripheral nervous systems. Brain and central nervous system neurons expressing neuroglobin are positioned close to many arteries within the brain parenchyma and can control smooth muscle contraction and, thus, tissue perfusion and vascular reactivity. Overall, reactions between NO and globin heme-iron contribute to vascular homeostasis by regulating vasodilatory NO signals and scaveging reactive species in cells of the mammalian vascular system. Here, we discuss how globin proteins affect vascular physiology with a focus on NO biology, and offer perspectives for future study of these functions.

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NOS, NO, and the Red Cell

Cited by 5 publications

References 109 publications

Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

Red Blood Cells as a “Central Hub” for Sulfide Bioactivity: Scavenging, Metabolism, Transport, and Cross-Talk with Nitric Oxide

The role of globins in cardiovascular physiology

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