The role of red cell eNOS in the regulation of vascular tone

红细胞 eNOS 在血管张力调节中的作用

• 批准号: 263779315
• 负责人: Professorin Dr. Miriam Margherita Cortese-Krott
• 金额: --
• 依托单位: Abteilung für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/263779315?language=en
• 关键词: role; red; cell; eNOS; regulation

Hypertension is the most important risk factor for cardiovascular disease. The kidney contributes to blood pressure control, mainly via the regulation of sodium and water homeostasis. In the kidney nitric oxide (NO) produced by the endothelial NO synthase (eNOS) was shown to regulate renal blood flow and thereby natriuresis, diuresis, and consequently blood pressure. However, the cellular source of the bioactive NO is still unknown. Interestingly, red blood cells (RBCs) were proposed to regulate blood flow by releasing NO bioactivity and inducing hypoxic vasodilation. Notably, hypoxic conditions prevail in the renal medulla, and thus RBC-mediated release of NO bioactivity may play a central role in medullary blood flow regulation. In the previous funding period, we found that RBC-specific eNOS KO mice had decreased circulating nitrite/nitrate levels and hypertension. Vice versa, reactivation of eNOS in the RBCs rescues the global eNOS KO mice from hypertension. The molecular mechanisms underpinning RBC eNOS-mediated blood pressure control and its role in the kidney are unknown. We hypothesize that RBC eNOS signaling controls the export of NO bioactivity in the kidney, which in turn contributes to the regulation of renal blood flow, sodium excretion, and blood pressure control. Mechanistically, RBC eNOS may regulate synthesis (under normoxic conditions) and export of NO metabolites (under hypoxic conditions) in the medulla, which then may induce vasodilation and regulation of blood flow. This study aims to analyze the role of red cell eNOS/sGC signaling in the regulation of renal blood flow and blood pressure. Specifically, we will analyze the role of red cell eNOS/sGC signaling (1) in the export of NO bioactivity, and regulation of vascular responses in resistive arteries in hypoxic conditions ex vivo; (2) in the regulation of renal blood flow ex vivo and in vivo in RBC eNOS KO and KI mice, as well as RBC sGC KO mice under homeostatic conditions and after treatment with angiotensin II (AngII); and (3) changes in eNOS/sGC signaling, HbNO formation and release of NO bioactivity in patients with hypertension. We anticipate that red cell eNOS/sGC signaling in the RBCs will play a significant role in the release of NO bioactivity, and hypoxic vasodilatatory effects of RBCs. Lack of RBC eNOS/sGC signaling will exacerbate AngII-induced decrease in medullary blood flow via a reduced export of eNOS-dependent NO bioactivity from the RBCs, thereby increasing hypertension. Compared to normotensive control, RBCs from hypertensive patients will show decreased vasodilatory function under hypoxia, which may be recovered by activating the eNOS/sGC signaling. These studies will reveal the link between red cell eNOS/sGC signaling, the release of NO bioactivity, and control of local blood flow in the kidney. Moreover, our studies may help identify novel clinical diagnostic markers and new druggable targets for treating hypertension.

高血压是心血管疾病最重要的危险因素。肾脏主要通过调节钠和水的体内平衡来控制血压。在肾脏中，由内皮NO合酶（eNOS）产生的一氧化氮（NO）显示出调节肾血流量，从而调节尿钠排泄、利尿，并因此调节血压。然而，生物活性NO的细胞来源仍然是未知的。有趣的是，红细胞（RBC）被认为是通过释放NO生物活性和诱导缺氧血管舒张来调节血流的。值得注意的是，缺氧条件下占主导地位的肾髓质，因此RBC介导的NO生物活性的释放可能在髓质血流调节中发挥核心作用。在之前的资助期间，我们发现RBC特异性eNOS KO小鼠的循环亚硝酸盐/硝酸盐水平和高血压降低。反之亦然，红细胞中eNOS的再活化拯救了整体eNOS KO小鼠免于高血压。支持RBC eNOS介导的血压控制的分子机制及其在肾脏中的作用尚不清楚。我们假设红细胞eNOS信号控制肾脏中NO生物活性的输出，这反过来又有助于调节肾血流量、钠排泄和血压控制。从机制上讲，RBC eNOS可以调节髓质中NO代谢物的合成（在常氧条件下）和输出（在缺氧条件下），然后可以诱导血管舒张和血流调节。本研究旨在分析红细胞eNOS/sGC信号通路在肾血流和血压调节中的作用。具体而言，我们将分析红细胞eNOS/sGC信号传导的作用：（1）在缺氧条件下输出NO生物活性和调节离体阻力动脉中的血管反应;（2）在RBC eNOS KO和KI小鼠以及在稳态条件下和用血管紧张素II（AngII）处理后的RBC sGC KO小鼠中离体和体内肾血流的调节;（3）高血压患者eNOS/sGC信号通路、HbNO生成和NO生物活性释放的变化。我们预期红细胞中的eNOS/sGC信号转导将在红细胞释放NO生物活性和低氧血管舒张效应中发挥重要作用。RBC eNOS/sGC信号传导的缺乏将通过减少eNOS依赖性NO生物活性从RBC的输出而加剧AngII诱导的髓血流量的减少，从而增加高血压。与正常血压对照相比，来自高血压患者的RBC在缺氧下将显示降低的血管舒张功能，这可以通过激活eNOS/sGC信号传导来恢复。这些研究将揭示红细胞eNOS/sGC信号传导、NO生物活性释放和肾脏局部血流控制之间的联系。此外，我们的研究可能有助于确定新的临床诊断标志物和治疗高血压的新药物靶点。