Effects of Circulating Endothelial Microvesicles and Aerobic Exercise on Cerebrovascular Inflammation in Chronic Kidney Disease

Chronic low-grade inflammation in chronic kidney disease (CKD) is associated with an increased risk of cardiovascular diseases (CVD), including stroke. Circulating endothelial microvesicles (EMVs), a subset of extracellular vesicles, have been linked to the etiology of ischemic stroke. Indeed, EMVs can cross the blood brain barrier and disrupt vascular function by promoting inflammation and oxidative stress. Regular aerobic exercise is an effective strategy for improving vascular health and, in turn, reducing stroke risk; potentially due to EMV reprogramming. The experimental aims of this study were to determine: 1) whether circulating EMVs are elevated in adults with CKD; 2) the effect of CKD-related EMVs on brain endothelial cell inflammation in vitro; and 3) the effect of regular aerobic exercise on the numerical and functional phenotype of EMVs in CKD patients. As part of an ongoing study 10 midlife adults were studied: five healthy adults (62±2 years; 4M/1F; eGFR: >60 ml·min - 1 ·1.73m - 2 ) and five adults with non-dialysis CKD (stage 3-4; 64±4 years; 4M/1F; eGFR: 46 ± 5 ml·min - 1 ·1.73m - 2 ). Circulating EMVs (CD144+) were quantified and isolated from plasma by flow cytometry. Human cerebral microvascular endothelial cells (HCMECs) were cultured and treated with EMVs isolated from either healthy or CKD adults at baseline and post-exercise (CKD adults only; aerobic exercise: 45 min/day, 65-80% heart rate reserve, 3x/week for 12 weeks). Circulating EMVs were ~30% higher (p<0.001) in CKD (883±79 EMV/µL) compared with healthy (698±39 EMV/µL) adults. EMVs from adults with CKD induced significantly greater proinflammatory cytokine release from HCMECs. Interleukin (IL)-6 (276.1±5.8 vs. 115.8±7.1 pg/mL) and IL-8 (2635.5±146.7 vs. 1351.9±44.7 pg/mL) release was ~150% (p=0.0001) higher in cells treated with EMVs from adults with CKD. Although total NF-κB p65 expression was not significantly different between groups (healthy: 220.9±10.8 AU vs CKD: 231.4±9.8 AU), CKD-related EMVs induced markedly higher (~95%) phosphorylated NF-κB p65 expression (88.6±8.3 vs. 45.5±3.2 AU), indicating heightened NF-κB activity consistent with increased IL-6 and IL-8 production. Twelve weeks of aerobic exercise did not significantly alter either circulating EMV levels (874±63 EMV/µL) in adults with CKD or the effect of EMVs on IL-6 (265.4±12.4 pg/mL) and IL-8 (2600.1±51.8 pg/mL) production and phosphorylated NF-κB p65 expression (80.5±7.4 AU) in vitro. In conclusion, these preliminary data indicate that circulating EMVs are elevated with CKD and induce a proinflammatory response in brain endothelial cells. Circulating EMVs may contribute to cerebrovascular inflammation and stroke risk in CKD. However, moderate-intensity aerobic exercise does not appear to affect EMVs in adults with CKD. It is possible that a higher exercise dose or longer duration may be needed elicit inflammation associated EMV changes in adults with CKD. NIH awards HL077450 and HL107715 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.