Global REACH 2018: High Altitude-Related Circulating Extracellular Microvesicles Promote a Proinflammatory Endothelial Phenotype In Vitro

Brewster, L. Madden, Anthony R. Bain, Vinicius P. Garcia, Noah M. DeSouza, Michael M. Tymko, Jared J. Greiner, and Philip N. Ainslie. Global REACH 2018: high altitude-related circulating extracellular microvesicles promote a proinflammatory endothelial phenotype in vitro. High Alt Med Biol. 00:000-000, 2023.Introduction: Ascent to high altitude (HA) can induce vascular dysfunction by promoting a proinflammatory endothelial phenotype. Circulating microvesicles (MVs) can mediate the vascular endothelium and inflammation. It is unclear whether HA-related MVs are associated with endothelial inflammation.Objectives: We tested the hypothesis that MVs derived from ascent to HA induce a proinflammatory endothelial phenotype.Methods: Ten healthy adults (8 M/2 F; age: 28 & PLUSMN; 2 years) residing at sea level (SL) were studied before and 4-6 days after rapid ascent to HA (4,300 m). MVs were isolated and enumerated from plasma by centrifugation and flow cytometry. Human umbilical vein endothelial cells were treated with MVs collected from each subject at SL (MV-SL) and at HA (MV-HA).Results: Circulating MV number significantly increased at HA (26,637 & PLUSMN; 3,315 vs. 19,388 & PLUSMN; 1,699). Although intracellular expression of total nuclear factor kappa beta (NF-& kappa;B; 83.4 & PLUSMN; 6.7 arbitrary units [AU] vs. 90.2 & PLUSMN; 6.9 AU) was not affected, MV-HA resulted in & SIM;55% higher (p < 0.05) active NF-& kappa;B (129.6 & PLUSMN; 19.8 AU vs. 90.7 & PLUSMN; 10.5 AU) expression compared with MV-SL. In addition, MV-HA induced higher interleukin (IL)-6 (63.9 & PLUSMN; 3.9 pg/ml vs. 53.3 & PLUSMN; 3.6 pg/ml) and IL-8 (140.2 & PLUSMN; 3.6 pg/ml vs. 120.7 & PLUSMN; 3.8 pg/ml) release compared with MV-SL, which was blunted with NF-& kappa;B blockade.Conclusions: Circulating extracellular MVs increase at HA and induce endothelial inflammation, potentially contributing to altitude-related vascular dysfunction.