Obesity-related elevation in circulating endothelial-derived extracellular microvesicles and endothelial fibrinolytic dysfunction

The capacity of the endothelium to release tissue-type plasminogen activator (t-PA) is markedly impaired in adults with obesity, underlying their increased thrombotic risk. Circulating endothelial cell-derived microvesicles (EMVs) are systemic modulators of vascular health and disease, and are elevated with obesity. The experimental aim of this study was to determine whether circulating EMVs are associated with obesity-related endothelial fibrinolytic dysfunction. Twenty-eight sedentary, midlife and older adults (45-71 yr) were studied: 14 normal-weight (7 M/7 F; age: 55 ± 4 yr; body mass index: 23.1 ± 1.6 kg/m²) adults and 14 adults with obesity (7 M/7 F; 57 ± 8 yr; 31.9 ± 2.9 kg/m²). 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 intrabrachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2.0-8.0 µg/min). Circulating EMV levels were ∼170% higher (<i>P</i> < 0.001) in adults with obesity (183 ± 58 EMV/µL) compared with normal-weight (68 ± 12 EMV/µL) adults. Endothelial t-PA release in response to BK was significantly lower (∼30%) in the adults with obesity (from 0.7 ± 3.6 to 35.9 ± 15.1 ng/100 mL tissue/min) versus normal-weight adults (-0.5 ± 2.3 to 68.4 ± 21.1 ng/100 mL tissue/min). Consequently, total t-PA release (area under the BK curve) was lower (∼35%; <i>P</i> = 0.007) in the adults with obesity (205 ± 118 ng/100 mL tissue vs. 325 ± 97 ng/100 mL tissue). Circulating EMVs were significantly and inversely associated with both peak t-PA release (<i>r</i> = -0.67; <i>P</i> = 0.0001) and total t-PA release to BK (<i>r</i> = -0.53; <i>P</i> = 0.004). In summary, obesity-related increase in circulating EMVs is associated with diminished endothelial t-PA release. Circulating EMVs may serve as a biomarker of fibrinolytic dysfunction in adults with obesity.<b>NEW & NOTEWORTHY</b> Obesity is associated with profound impairment in the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA), the primary mechanism underlying endogenous thrombolysis. Circulating endothelial cell-derived extracellular vesicles (EMVs) have been linked to endothelial dysfunction. This study demonstrates that circulating EMVs are elevated in adults with obesity and are associated with reduced endothelial t-PA release. Circulating EMVs represent a novel systemic biomarker of obesity-related endothelial fibrinolytic dysfunction and, in turn, thrombotic risk.