Aging Is Associated with a Circulating Endothelial Cell-Derived Microvesicle Phenotype that Increases Cerebral Oxidative Stress

Aging is associated with increased risk and prevalence of ischemic stroke. Vascular oxidative stress impairs cell function and is considered to be an important mechanism underlying the age-related increase in cerebrovascular accidents (CVA). However, the direct, and indirect, effects of aging on endothelial cell oxidative stress are complex and not completely understood. Increase in reactive oxygen species coupled with reduced anti-oxidative capacity creates a prooxidative endothelial phenotype resulting in impaired cell dysfunction, accelerated unprogrammed cell death and, in turn, CVAs. Several recent seminal studies have demonstrated that circulating endothelial cell- derived microvesicles (EMVs) are etiologically involved in the development and progression of endothelial dysfunction and CVA. We have previously demonstrated that aging is associated with increased circulating levels of EMVs. The aim of this study was to determine, in vitro, the effect of circulating EMVs isolated from young and older adults on brain endothelial cell oxidative stress. We hypothesized that EMVs from older adults would induce a prooxidative endothelial phenotype. As part of an ongoing study, 16, non-obese, normotensive, sedentary adults were studied: 8 young (5M/3F; age: 25±1 yr) and 8 older (4M/4F; 69±2 yr). EMV identification (CD144+) and isolation from peripheral blood was performed by flow cytometry. Human cerebral microvascular endothelial cells (hCMECs) were cultured and separately treated with EMVs from each subject for 24 hours. Intracellular reactive oxygen species (ROS) production was determined using CellROX Deep Red Reagent. Circulating EMVs were ~75% higher (P=0.002) in older (140±13 EMV/μL) vs young (82±8 EMV/μL) adults. Cellular ROS was significantly higher (~40%) in hCMECs treated with EMVs from older (141±14%) compared with young (101±5%) adults. In addition, intracellular expression of key anti-oxidant proteins were significantly lower in cells treated with EMVs from older adults. Cell expression of both superoxide dismutase 1 (SOD-1: 20.6±2.3 vs 36.3±3.1 AU) and catalase (17.1±1.9 vs 27.5±3.0 AU) were ~35% lower in hCMECs treated with EMVs from older adults. Moreover, intracellular ROS was inversely and significantly correlated with SOD-1 (r=-0.54; P=0.03) and catalase (r=-0.62; P=0.01) expression reflective of the cellular oxidative milieu. In conclusion, circulating EMVs may contribute to the increased risk of ischemic stroke with aging by increasing brain endothelial cell oxidative stress and reducing oxidative defense mechanisms. EMVs may represent a viable therapeutic target for mitigating the risk of CVA with aging. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.