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

• Applicants: Professorin Dr. Miriam Margherita Cortese-Krott; Professor Dr. Johannes Stegbauer
• Subject Area: Cardiology, Angiology ; Anatomy and Physiology ; Pharmacology
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263779315

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.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Doris Koesling