Abstract 13111: Circulating Extracellular Microvesicles: Mediators of Altitude-Related Vascular Inflammation

Abstract

Ascent to high altitude can adversely affect cardio- and cerebrovascular health, particularly in those with pre-existing disease. Pathologic vascular responses to acute and subacute high altitude exposure include, endothelial dysfunction, cerebral and pulmonary edema as well as pulmonary hypertension. Changes in vascular endothelial cell function, most notably the induction of a proinflammatory endothelial phenotype, is thought to be an underlying factor. Endothelial inflammation can induce cerebral edema in stroke and promote pulmonary edema. The mechanisms underlying high-altitude related vascular inflammation remain unclear. The vascular endothelium is significantly influenced by circulating cell-derived microvesicles (MVs). MVs are small (100-1000 nm) membrane vesicles that are released by various cell types (e.g. endothelial, platelets, leukocytes) in response to a myriad of physiologic and pathologic stimuli including hypoxia. Circulating MVs have emerged as biomarkers and mediators of endothelial inflammation. We tested the hypothesis that ascent to high altitude induces a proinflammatory circulating MV phenotype. Ten healthy adults (8 M/2 F; age: 28 + 2 yr ) residing at sea level (Kelowna, BC, Canada) were studied prior to and 4-6 days after ascending to high altitude (Cerro de Pasco, Peru; 4300 m). Circulating MVs were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with MVs collected from each subject at sea level and altitude. Circulating MVs were significantly higher at altitude vs sea level (26637 + 3315 vs19388 + 1699 MV/μL). Altitude-related MVs induced higher (~25%; P<0.05) release of interleukin (IL)-6 (63.9±3.9 vs 53.3±3.6 pg/mL) and IL-8 (140.2±3.6 vs 120.7±3.8 pg/mL) compared with MVs harvested at sea level. Although intracellular expression of total NF-κB p65 (83.4 + 6.7 vs 90.2 + 6.9 AU) was not significantly affected, high altitude-MVs resulted in ~55% higher (P<0.05) cell expression of p-NF-κB p65 (active NF-κB: 129.6 + 19.8 vs 90.7 + 10.5 AU) than sea level-MVs. Circulating extracellular MVs increase at high altitude and induce endothelial inflammation, potentially contributing to altitude-related vascular pathologies.