Details

Autor(en) / Beteiligte

• Zhuge, Zhengbing
• McCann Haworth, Sarah
• Nihlén, Carina
• Carvalho, Lucas Rannier R.A.
• Heuser, Sophia K.
• Kleschyov, Andrei L.
• Nasiell, Josefine
• Cortese-Krott, Miriam M.
• Weitzberg, Eddie
• Lundberg, Jon O.
• Carlström, Mattias

Titel

Red blood cells from endothelial nitric oxide synthase-deficient mice induce vascular dysfunction involving oxidative stress and endothelial arginase I

Ist Teil von

• Redox biology, 2023-04, Vol.60, p.102612-102612, Article 102612

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Nitric oxide bioactivity (NO) from endothelial NO synthase (eNOS) importantly contributes to the maintenance of vascular homeostasis, and reduced eNOS activity has been associated with cardiovascular disease. Emerging evidence suggests interaction(s) between red blood cells (RBCs) and the endothelium in vascular control; however, the specific role of RBC eNOS is less clear. We aimed to investigate the hypothesis that a lack of RBC eNOS induces endothelial dysfunction. RBCs from global eNOS knockout (KO) and wildtype (WT) mice were co-incubated ex vivo overnight with healthy mouse aortic rings, followed by functional and mechanistic analyses of endothelium-dependent and independent relaxations. RBCs from eNOS KO mice induced endothelial dysfunction and vascular oxidative stress, whereas WT RBC did not. No differences were observed for endothelium-independent relaxations. This eNOS KO RBC-induced endothelial dysfunctional phenotype was prevented by concomitant co-incubation with reactive oxygen species scavenger (TEMPOL), arginase inhibitor (nor-NOHA), NO donor (detaNONOate) and NADPH oxidase 4 (NOX4) inhibitor. Moreover, vessels from endothelial cell-specific arginase 1 KO mice were resistant to eNOS KO-RBC-induced endothelial dysfunction. Finally, in mice aortae co-incubated with RBCs from women with preeclampsia, we observed a significant reduction in endothelial function compared to when using RBCs from healthy pregnant women or from women with uncomplicated gestational hypertension. RBCs from mice lacking eNOS, and patients with preeclampsia, induce endothelial dysfunction in adjacent blood vessels. Thus, RBC-derived NO bioactivity acts to prevent induction of vascular oxidative stress occurring via RBC NOX4-derived ROS in a vascular arginase-dependent manner. Our data highlight the intrinsic protective role of RBC-derived NO bioactivity in preventing the damaging potential of RBCs. This provides novel insight into the functional relationship between RBCs and the vasculature in health and cardiovascular disease, including preeclampsia. [Display omitted] •Using a novel ex vivo model, we investigated the impact of RBC eNOS on erythrocrine function and vascular homeostasis.•RBCs from eNOS knockout mice induce endothelial dysfunction in healthy vessels, due to the induction of an imbalance between NO and ROS within the vascular microenvironment.•Similar to eNOS knockout mice, RBCs from patients with preeclampsia induce endothelial dysfunction, which was not observed by RBC from women with gestational hypertension.•These findings provide a better understanding of the crucial role of RBC NO and ROS balance in mediation of cardiovascular disease pathogenesis.•Targeting RBC NO homeostasis could be a novel therapeutic approach for endothelial dysfunction-related cardiovascular diseases.