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Extracellular Endothelial Microvesicles Causative Agents in Obesity‐Related Endothelial Dysfunction
Author(s) -
Garcia Vinicius,
Brewster L. Madden,
Fandl Hannah,
Stockelman Kelly,
DeSouza Noah,
Treuth J. William,
Greiner Jared,
Davy Kevin,
DeSouza Christopher
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03671
Subject(s) - endothelial dysfunction , medicine , microvesicles , inflammation , nitric oxide , cd31 , extracellular , endocrinology , immunology , obesity , homeostasis , microvesicle , angiogenesis , chemistry , biochemistry , microrna , gene
Obesity is associated with increased cardiovascular disease morbidity and mortality. Moreover, obese individuals demonstrate accelerated rates of atherosclerosis, as well as increased incidence of myocardial infarction and stroke. Extracellular microvesicles, particularly endothelial cell‐derived microvesicles (EMVs), are seminal functional modulators of vascular health and disease. We have previously demonstrated that EMVs are elevated with obesity and associated with endothelial dysfunction, although the underlying mechanisms are unknown. The experimental aim of this study was to determine the effects of EMVs isolated from obese adults on endothelial cell inflammation, apoptosis and nitric oxide (NO) production. Twenty‐four middle‐aged adults were studied: 12 normal weight (8M/4F; BMI: 24.4 + 0.3 kg/m 2 ; EMVs: 85 + 13 EMV/µL) and 12 obese (6M/6F; BMI: 31.1 + 0.4 kg/m 2 ; EMVs: 160 + 18 EMV/µL). All subjects were sedentary, non‐smokers, normotensive, normolipidemic, non‐diabetic and free of overt coronary artery disease. EMVs (CD31+/CD42b‐) were identified, enumerated, and isolated from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with EMVs from either normal weight or obese adults. EMVs from obese adults induced significantly greater release of both IL‐6 (108.2±2.3 vs 90.9±2.9 pg/mL) and IL‐8 (74.5±2.9 vs 59.5±3.3 pg/mL) from endothelial cells vs EMVs from normal weight adults. Intracellular expression of total NF‐kB p65 was not significantly different in cells treated with EMVs from the normal weight (78.2 + 9.3 AU) or obese (86.5 + 8.7 AU) subjects. However, EMVs from obese subjects induced ~25% higher expression of phosphorylated‐NF‐kB p65 (Ser536; active NF‐kB) (145.0 + 9.8 vs 114.5 + 8.8 AU). There were no significant differences in cellular expression of total p38‐MAPK (190.6 + 18.4 vs 163.2 + 9.5 AU) and caspase‐3 (250.9±20.9 vs 283.0±19.4 AU) in cells treated with EMVs from normal weight and obese adults. However, EMVs from obese adults induced significantly higher (~50%) expression of phospho‐p38‐MAPK(15.4 + 1.6 vs 9.2 + 0.7 AU) and active caspase‐3 (168.2±18.9 vs 107.8±11.7 AU) than EMVs from normal weight adults. Total eNOS expression was not significantly different between cells treated with EMVs from normal weight (110.9 + 12.0 AU) and obese (112.8 + 14.4 AU) adults; however, p‐eNOS (Ser1177) expression was ~50% lower (P<0.05) in the cells treated with EMVs from obese adults (18.4 + 3.4 vs 34.6 + 2.8 AU). Consistent with changes in p‐eNOS, NO production was ~20% lower (6.9 + 0.4 vs 8.7 + 0.2 mmol/L) in cells treated with EMVs from obese adults. Increased inflammation, apoptosis susceptibility and decreased eNOS activity and NO production renders the vascular endothelium prone to atherosclerosis and thrombosis. Circulating EMVs likely contribute to the proatherogenic endothelial phenotype and, in turn, the increased incidence of cardiovascular disease with obesity.