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Red blood cells (RBCs) have traditionally been seen as simple carriers of gases and nutrients in the body. One important non-canonical function of RBCs in the cardiovascular system is the regulation of nitric oxide (NO) metabolism. It has been shown that RBCs can scavenge NO, transport NO metabolites and produce NO in hypoxic conditions, thereby inducing hypoxic vasodilation. RBCs also express endothelial nitric oxide synthase (eNOS). However, the physiological significance of RBC eNOS has been controversial for many years. This review article provides a comprehensive overview of the experimental research on RBC eNOS signalling in vivo. The data show that RBC eNOS signalling modulates intracellular NO production and NO-haem levels, as well as participating in extracellular paracrine NO metabolite signalling, which contributes to regulating peripheral vascular resistance, blood pressure and cardioprotection. Additionally, this article explores the molecular mechanisms of sytemic regulation mediated by RBC eNOS and the implications of RBC eNOS in cardiovascular health and disease.
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http://dx.doi.org/10.1111/bph.16230 | DOI Listing |
Nitric Oxide
September 2025
Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA; Translational Science Center, Wake Forest University, Winston-Salem, NC 27109, USA. Electronic address:
We recently demonstrated a rapid reaction between labile ferric heme and nitric oxide (NO) in the presence of reduced glutathione (GSH) or other small thiols in a process called thiol-catalyzed reductive nitrosylation, yielding a novel signaling molecule, labile nitrosyl ferrous heme (NO-ferroheme), which we and others have shown can regulate vasodilation and platelet homeostasis. Red blood cells (RBCs) contain high concentrations of GSH, and NO can be generated in the RBC via nitrite reduction and/or RBC endothelial nitric oxide synthase (eNOS) so that NO-ferroheme could, in principle, be formed in the RBC. NO-ferroheme may also form in other cells and compartments, including in plasma, where another small and reactive thiol species, hydrogen sulfide (HS/HS), is also present and may catalyze NO-ferroheme formation akin to GSH.
View Article and Find Full Text PDFNitric Oxide
August 2025
Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. Electronic address:
Background: Red blood cells (RBCs) express functional endothelial nitric oxide synthase (eNOS), which regulates blood pressure (BP) independently of eNOS in endothelial cells (ECs) and provides cardioprotection during acute myocardial infarction (AMI). The functional role of RBC- and EC- eNOS in anemia remains unknown. This study evaluated the effects of RBC- or EC-specific eNOS deletion on hemodynamics and cardiac function in blood loss anemia.
View Article and Find Full Text PDFMechanobiol Med
September 2025
Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Dr, College Park, MD, 20742, USA.
Nitric oxide (NO) is a key signaling molecule in maintaining cardiovascular health. While endothelial cells were initially thought to exclusively contain endothelial nitric oxide synthase (eNOS), an enzyme that produces NO, recent evidence suggests that red blood cells (RBC) also contain functional eNOS that impacts cardiovascular function. However, the mechanisms driving RBC eNOS activation are not well understood.
View Article and Find Full Text PDFFront Physiol
May 2025
School of Medicine, ShaoXing University, Shaoxing, Zhejiang Province, China.
Once considered passive carriers of oxygen, erythrocytes are now understood to play active roles in regulating oxygen homeostasis and redox balance. This review examines the molecular mechanisms through which red blood cells adapt to hypoxic conditions, including nitric oxide (NO)-driven changes in membrane properties, βCys93-dependent S-nitrosylation, adenosine-induced activation of glycolysis, and the development of hypoxic memory via eENT1 degradation. Enzymes such as RBC eNOS, CYB5R3, and G6PD are essential for maintaining NO availability and redox balance by controlling redox state and NADPH synthesis.
View Article and Find Full Text PDFMediators Inflamm
May 2025
Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Republic of Korea.
The role of the gut microbiomes has been emphasized in the pathogenesis of obese asthma (OA). However, the molecular mechanism of airway dysfunction underlying OA has not yet been fully elucidated. The effects of microbiomes on arginine metabolism in relation to lung functions and a novel method for delivering arginine to lung tissue based on arginine-loaded red blood cell (RBC)-derived nanovesicles (NVs) (NV) will be investigated.
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