Elevated Circulating Endothelial-Derived Microvesicles are Associated with Obesity-Related Fibrinolytic Dysfunction

Adults with obesity demonstrate accelerated rates of atherosclerosis, as well as increased incidence of myocardial infarction and stroke. As such, obesity reduces the number of years lived free of cardiovascular disease (CVD) and increases the number of years lived with CVD, contributing to increased morbidity and mortality risk across all ages. Experimental and clinical studies indicate that a prothrombotic endothelial phenotype is a major consequence of increased adiposity and a central mechanism underlying obesity-related atherothrombotic vascular events. Indeed, the capacity of the endothelium to release tissue-type plasminogen activator (t-PA) is markedly impaired in adults with obesity; however, the mechanisms underlying this dysfunction are complex and not well-defined. We have previously demonstrated that extracellular microvesicles, particularly endothelial cell-derived microvesicles (EMVs), are seminal, systemic modulators of vascular health and disease. The purpose of this study was to determine: 1) if circulating EMV levels are elevated in adults with obesity, independent of other cardiometabolic risk factors; and if so, 2) whether circulating EMVs are associated with obesity-related endothelial fibrinolytic dysfunction. Twenty-eight sedentary, mid-life and older adults (45-71 years) were studied: 14 normal weight (7M/7F; age: 55+1 yr; BMI: 23.1+0.4 kg/m2; body fat: 27.4+2.3%) and 15 obese (7M/7F; age: 57+2 yr; BMI: 31.9+0.8 kg/m2; body fat: 39.8+2.4%). All subjects were and free of other cardiometabolic risk factors and overt disease. EMV identification (CD144+) and concentration in peripheral blood were determined by flow cytometry. Endothelial release of t-PA was determined, in vivo, in response to intra-brachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2.0-8.0 µg/min). Circulating EMV levels were ~170% higher (p<0.001) in obese (183±16 EMV/µL) compared with normal weight (68±3 EMV/µL) adults. As expected, endothelial t-PA release in response to BK was significantly blunted (~30%) in the adults with obesity (from 0.7±0.9 to 39.8±5.3 ng/100mL tissue/min) vs normal weight adults (-0.5±0.6 to 67.5±6.1 ng/100mL tissue/min). Consequently, total t-PA release (area under the BK curve) was lower (~30%; P=0.03) in the adults with obesity (213±33 ng/100mL tissue vs 314±29 ng/100mL tissue). Circulating EMVs were significantly and inversely associated with both peak t-PA release (r=-0.57; P=0.002) and total t-PA release to BK (r=-0.47; P=0.01). In summary, obesity-related increase in circulating EMVs is associated with impaired endothelial t-PA release. EMVs may serve as a biomarker of, and contribute to, obesity-related fibrinolytic dysfunction and, in turn, increased risk of thrombotic events. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.