红细胞和内皮型一氧化氮合酶独立调节循环中一氧化氮代谢物和血压。
Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure.
机构信息
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology (F.L., T.S., S.K.H., J.L., A.L.B., F.B., E.P., B.H., L.V., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Department of Cardiology Pneumology and Angiology (T.S., M.K., M.M.C.-K.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
出版信息
Circulation. 2021 Sep 14;144(11):870-889. doi: 10.1161/CIRCULATIONAHA.120.049606. Epub 2021 Jul 7.
BACKGROUND
Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) through 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 RBC eNOS compared with EC eNOS for vascular hemodynamics and nitric oxide 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 2 founder lines carrying a floxed eNOS (eNOS) for Cre-inducible knockout (KO), and gene construct with an inactivated floxed/inverted exon (eNOS) 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 in ECs (EC eNOS KO or EC eNOS KI mice). Vascular function, hemodynamics, and nitric oxide 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, and increased systolic and diastolic blood pressure. RBC eNOS KO mice showed no alterations in acetylcholine-mediated dilation or flow-mediated dilation but were hypertensive. Treatment with the nitric oxide synthase inhibitor -nitro-l-arginine methyl ester further increased blood pressure in RBC eNOS KOs, demonstrating that eNOS in both ECs and RBCs contributes to blood pressure regulation. Although 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 than in EC eNOS KOs. Reactivation of eNOS in ECs or RBCs rescues the hypertensive phenotype of the eNOS mice, whereas 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.
背景
目前的研究模式表明，血管壁内皮细胞（ECs）通过内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）是调节血流和血压的主要因素。然而，红细胞（RBCs）也携带具有催化活性的 eNOS，但它的作用存在争议，尚未明确。本研究旨在阐明 RBC eNOS 相对于 EC eNOS 对血管血液动力学和一氧化氮代谢的功能意义。
方法
我们通过细胞特异性 Cre 诱导的基因失活或再激活，生成了组织特异性的 eNOS 功能丧失和获得功能模型。我们创建了 2 个携带 floxed eNOS（eNOS）的启动子线，用于 Cre 诱导的基因敲除（KO），以及带有失活的 floxed/倒置外显子（eNOS）的基因构建体，用于 Cre 诱导的基因敲入（KI），这分别允许在红细胞（RBC eNOS KO 或 RBC eNOS KI 小鼠）或 ECs（EC eNOS KO 或 EC eNOS KI 小鼠）中靶向敲除或再激活 eNOS。我们在体外用血管功能、血液动力学和一氧化氮代谢比较来进行研究。
结果
EC eNOS KO 表现出明显受损的主动脉乙酰胆碱舒张反应、丧失血流介导的舒张和升高的收缩压和舒张压。RBC eNOS KO 小鼠在乙酰胆碱介导的舒张或血流介导的舒张方面没有变化，但表现出高血压。一氧化氮合酶抑制剂 -硝基-L-精氨酸甲酯的治疗进一步增加了 RBC eNOS KO 小鼠的血压，表明 ECs 和 RBCs 中的 eNOS 均有助于血压调节。尽管 EC eNOS KO 和 RBC eNOS KO 小鼠的血浆硝酸盐和亚硝酸盐浓度均较低，但 RBC eNOS KO 小鼠 RBC 中结合的 NO 水平低于 EC eNOS KO 小鼠。ECs 或 RBCs 中 eNOS 的再激活挽救了 eNOS 小鼠的高血压表型，而只有 RBC eNOS KI 小鼠的结合态 NO 水平得到恢复。
结论
这些数据表明，ECs 和 RBCs 中的 eNOS 独立地有助于血压的动态平衡。
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