Circulating endothelial extracellular vesicles progressively increase with age and are associated with endothelial vasodilator dysfunction.

Abstract

Aging is associated with a progressive increase in risk and prevalence of cardiovascular disease (CVD). Circulating extracellular vesicles, particularly endothelial cell-derived microvesicles (EMVs), have been linked to the development and progression of endothelial dysfunction and CVD. The purpose of this study was to determine 1) if circulating EMV levels increase with age, independent of other cardiometabolic risk factors; and if so, 2) whether circulating EMVs are associated with age-related endothelial vasodilator dysfunction. Forty healthy, nonobese, normotensive, sedentary males were studied: 12 young (age: 27 ± 5 yr), 14 midlife (51 ± 5 yr), and 14 older (67 ± 5 yr). EMV identification (CD31⁺/42b^-) and concentration in peripheral blood were determined by flow cytometry. Forearm blood flow (FBF: via plethysmography) was assessed in response to intra-arterial infusions of acetylcholine and sodium nitroprusside. Circulating EMV levels were significantly and progressively higher across the young, midlife, and older groups (54 ± 14 vs. 101 ± 30 vs. 132 ± 54 EMV/µL, respectively). FBF response to acetylcholine was significantly lower (∼30%) in the midlife (4.5 ± 0.8 to 13.5 ± 3.3 mL/100 mL tissue/min) and older (4.2 ± 1.0 to 11.5 ± 2.8 mL/100 mL tissue/min) vs. young (from 5.2 ± 1.1 to 17.2 ± 4.9 mL/100 mL tissue/min) group. Circulating EMVs were positively associated with age (r = 0.69; P < 0.001) and inversely associated with endothelial vasodilation (peak FBF to acetylcholine: r = -0.51; and total FBF to acetylcholine: r = -0.48; P = 0.02). Aging, independent of other cardiometabolic risk factors, is associated with progressively elevated circulating levels of EMVs in healthy males. Circulating EMVs may serve as a biomarker of, and potential contributor to, age-related endothelial dysfunction and vascular disease risk.NEW & NOTEWORTHY Aging is associated with progressive decline in endothelium-dependent vasodilation. Mechanisms underlying this decline in endothelial function are not fully understood. Circulating endothelial cell-derived extracellular vesicles (EMVs) have been linked to endothelial dysfunction. The results of the study demonstrate that circulating EMVs increase with age in healthy males and are associated with endothelial vasodilator dysfunction. Circulating EMVs represent a novel systemic biomarker, and potential mediator, of age-related decline in endothelium-dependent vasodilation.