TY - BOOK

T1 - Mitochondrial function and the role of reactive oxygen species in microvascular skeletal muscle endothelial cells derived from rat and human. Microvascular endothelial cells – Beauty or the Beast?

AU - Hansen, Camilla Collin

N1 - CURIS 2022 NEXS 087

PY - 2022

Y1 - 2022

N2 - Cardiovascular disease is highly prevalent and associated with the highest mortality rate in the Western world. Impaired function of endothelial cells, located on the inside of all blood vessels, is one of the main causes of cardiovascular disease. It has been proposed, that individuals with cardiovascular disease have impaired mitochondrial function and increased mitochondrial formation of reactive oxygen species (ROS), but evidence for this proposition is lacking. Enhanced ROS formation in endothelial cells is critical, as ROS readily react with and inactivate nitric oxide (NO), a key player in the control of vascular tone. Enhanced knowledge of mitochondrial function and ROS formation in cardiovascular disease is important for the molecular understanding of endothelial dysfunction and for the development of novel treatment strategies in cardiovascular disease. This thesis focuses on hypertension and addresses the role of mitochondria in endothelial dysfunction with a specific focus on redox balance, NO bioavailability and metabolism in skeletal muscle microvascular endothelial cells. The studies of this thesis include data on primary endothelial cells isolated from skeletal muscle of both rats and humans, as well as data from an invivo human study, in which the impact of regular exercise training was assessed. Moreover, to assess the role of mitochondria derived ROS for endothelial phenotype and function, cells were subjected to chronic treatment with the mitochondrial antioxidant, Mitoquinone mesylate (MitoQ).Main findings in this thesis were that hypertension was associated with elevatedmitochondrial ROS (Study II and Study IV) with an associated lower availability of NO in skeletal muscle microvascular endothelial cells (Study II). The higher ROS production from the mitochondria in human endothelial cells in patients with hypertension correlated with endothelial function determined in vivo by acetylcholine infusion (Study III). Finally, there was an improved redox balance and potential for prostaglandin synthesis with exercise training and with MitoQtreatment. These interventions were also associated with a reduction in glycolytic metabolism in the endothelial cells.In conclusion, this thesis has for the first time established that, in hypertension, skeletal muscle derived microvascular endothelial cells present a higher mitochondrial ROS formation, lower antioxidant levels and a consequent lower NO bioavailability. Exercise training and treatment with MitoQ can ameliorate this redox imbalance. Future studies should provide further insight into the specific molecular signalling pathways underpinning these regulatory mechanisms.

AB - Cardiovascular disease is highly prevalent and associated with the highest mortality rate in the Western world. Impaired function of endothelial cells, located on the inside of all blood vessels, is one of the main causes of cardiovascular disease. It has been proposed, that individuals with cardiovascular disease have impaired mitochondrial function and increased mitochondrial formation of reactive oxygen species (ROS), but evidence for this proposition is lacking. Enhanced ROS formation in endothelial cells is critical, as ROS readily react with and inactivate nitric oxide (NO), a key player in the control of vascular tone. Enhanced knowledge of mitochondrial function and ROS formation in cardiovascular disease is important for the molecular understanding of endothelial dysfunction and for the development of novel treatment strategies in cardiovascular disease. This thesis focuses on hypertension and addresses the role of mitochondria in endothelial dysfunction with a specific focus on redox balance, NO bioavailability and metabolism in skeletal muscle microvascular endothelial cells. The studies of this thesis include data on primary endothelial cells isolated from skeletal muscle of both rats and humans, as well as data from an invivo human study, in which the impact of regular exercise training was assessed. Moreover, to assess the role of mitochondria derived ROS for endothelial phenotype and function, cells were subjected to chronic treatment with the mitochondrial antioxidant, Mitoquinone mesylate (MitoQ).Main findings in this thesis were that hypertension was associated with elevatedmitochondrial ROS (Study II and Study IV) with an associated lower availability of NO in skeletal muscle microvascular endothelial cells (Study II). The higher ROS production from the mitochondria in human endothelial cells in patients with hypertension correlated with endothelial function determined in vivo by acetylcholine infusion (Study III). Finally, there was an improved redox balance and potential for prostaglandin synthesis with exercise training and with MitoQtreatment. These interventions were also associated with a reduction in glycolytic metabolism in the endothelial cells.In conclusion, this thesis has for the first time established that, in hypertension, skeletal muscle derived microvascular endothelial cells present a higher mitochondrial ROS formation, lower antioxidant levels and a consequent lower NO bioavailability. Exercise training and treatment with MitoQ can ameliorate this redox imbalance. Future studies should provide further insight into the specific molecular signalling pathways underpinning these regulatory mechanisms.

KW - Faculty of Science

KW - Mitochondrial function

KW - Microvascular endothelial cells

KW - Rat

KW - Human

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/1pioq0f/alma99124193433505763

M3 - Ph.D. thesis

BT - Mitochondrial function and the role of reactive oxygen species in microvascular skeletal muscle endothelial cells derived from rat and human. Microvascular endothelial cells – Beauty or the Beast?

PB - Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen

CY - Copenhagen

ER -