Lu Peng1, Yu Li1, Xinwei Li1, Yunhui Du1, Linyi Li1, Chaowei Hu1, Jing Zhang1, Yanwen Qin1, Yongxiang Wei2, Huina Zhang3. 1. Key Laboratory of Upper Airway Dysfunction-related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Beijing, 100029, China. 2. Department of Otolaryngology-Head and Neck Surgery, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Beijing, 100029, China. wei__yongxiang@126.com. 3. Key Laboratory of Upper Airway Dysfunction-related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Beijing, 100029, China. whinnerzhn@126.com.
Abstract
PURPOSE: Intermittent hypoxia (IH), a main characteristic of obstructive sleep apnea (OSA) syndrome, has been known as a dominant cause of OSA-related endothelial dysfunction and hypertension. However, the underlying mechanism still remains unclear. Extracellular vesicles (EVs), small vesicles secreted by various cells, can be absorbed by endothelial cells and then influence vascular function. The aim of this research is to clarify whether and how EVs shedding from red blood cells (RBCs) are involved in IH-induced endothelial dysfunction. METHODS: EVs were extracted by ultracentrifugation. After the identification of property and purity, EVs from IH-exposed RBCs (IH REVs) and normoxia-exposed RBCs (NOR REVs) or from OSA and non-OSA patient RBCs were utilized to treat C57BL/6 mouse aortas or human umbilical vein endothelial cells (HUVECs) for mechanistic exploration. RESULTS: Functional results demonstrated that REVs from OSA patients dramatically impaired endothelium-dependent relaxations (EDRs). Similarly, in vivo and ex vivo studies showed that IH REVs caused significant endothelial dysfunction compared to control group. Further results presented that IH REVs blocked endothelial nitric oxide synthase (eNOS) phosphorylation through inhibiting PI3K/Akt pathway and enhanced endothelin-1 (ET-1) expression through activating Erk1/2 pathway in endothelial cells. Meanwhile, endothelial dysfunction caused by IH REVs was reversed by Akt activator SC79 as well as Erk kinase inhibitor PD98059, suggesting that PI3K/Akt/eNOS and Erk1/2/ET-1 pathways were implicated in IH REV-induced impaired EDRs. CONCLUSIONS: This study reveals a novel role of REVs in endothelial dysfunction under IH and dissects the relevant mechanism involved in this process, which will help to establish a comprehensive understanding of OSA or IH-related endothelial dysfunction from a new scope.
PURPOSE: Intermittent hypoxia (IH), a main characteristic of obstructive sleep apnea (OSA) syndrome, has been known as a dominant cause of OSA-related endothelial dysfunction and hypertension. However, the underlying mechanism still remains unclear. Extracellular vesicles (EVs), small vesicles secreted by various cells, can be absorbed by endothelial cells and then influence vascular function. The aim of this research is to clarify whether and how EVs shedding from red blood cells (RBCs) are involved in IH-induced endothelial dysfunction. METHODS: EVs were extracted by ultracentrifugation. After the identification of property and purity, EVs from IH-exposed RBCs (IH REVs) and normoxia-exposed RBCs (NOR REVs) or from OSA and non-OSA patient RBCs were utilized to treat C57BL/6 mouse aortas or human umbilical vein endothelial cells (HUVECs) for mechanistic exploration. RESULTS: Functional results demonstrated that REVs from OSA patients dramatically impaired endothelium-dependent relaxations (EDRs). Similarly, in vivo and ex vivo studies showed that IH REVs caused significant endothelial dysfunction compared to control group. Further results presented that IH REVs blocked endothelial nitric oxide synthase (eNOS) phosphorylation through inhibiting PI3K/Akt pathway and enhanced endothelin-1 (ET-1) expression through activating Erk1/2 pathway in endothelial cells. Meanwhile, endothelial dysfunction caused by IH REVs was reversed by Akt activator SC79 as well as Erk kinase inhibitor PD98059, suggesting that PI3K/Akt/eNOS and Erk1/2/ET-1 pathways were implicated in IH REV-induced impaired EDRs. CONCLUSIONS: This study reveals a novel role of REVs in endothelial dysfunction under IH and dissects the relevant mechanism involved in this process, which will help to establish a comprehensive understanding of OSA or IH-related endothelial dysfunction from a new scope.
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