Emergence of AnnexinVpos CD31neg CD42blow/neg extracellular vesicles in plasma of humans at extreme altitude

Abstract

Background Hypobaric hypoxia has been reported to cause endothelial cell and platelet dysfunction implicated in the formation of microvascular lesions, and in its extremes may contribute to vascular leakage in high altitude pulmonary edema or blood brain barrier disruption leading to cerebral micro-hemorrhage (MH). Platelet function in the development of microvascular lesions remained ill defined, and is still incompletely understood. In this study platelet- and endothelial cell-derived extracellular vesicles (PEV and EEV, respectively) and cell adhesion molecules were characterized in plasma samples of members of a high altitude expedition to delineate the contribution of platelets and endothelial cells to hypobaric hypoxia-induced vascular dysfunction. Methods and findings In this observational study, platelet and endothelial cell-derived extracellular vesicles were analysed by flow-cytometry in plasma samples from 39 mountaineers participating in a medical research climbing expedition to Himlung Himal, Nepal, 7,050m asl. Megakaryocyte/platelet-derived AnnexinV pos , PECAM-1 (CD31) and glycoprotein-1b (GP1b, CD42b) positive extracellular vesicles (PEV) constituted the predominant fraction of EV in plasma samples up to 6,050m asl. Exposure to an altitude of 7,050m led to a marked decline of CD31 pos CD42 neg EEV as well as of CD31 pos CD42b pos PEV at the same time giving rise to a quantitatively prevailing CD31 neg CD42b low/neg subpopulation of AnnexinV pos EV. An almost hundredfold increase in the numbers of this previously unrecognized population of CD31 neg CD42b low/neg EV was observed in all participants reaching 7,050m asl. Conclusions The emergence of CD31 neg CD42b low/neg EV was observed in all participants and thus represents an early hypoxic marker at extreme altitude. Since CD31 and CD42b are required for platelet-endothelial cell interactions, these hypobaric hypoxia-dependent quantitative and phenotypic changes of AnnexinV pos EV subpopulations may serve as early and sensitive indicators of compromised vascular homeostasis.

Where Metabolism Meets Senescence: Focus on Endothelial Cells

“…To address this issue, the field is moving toward more specific approaches allowing the deconvolution of complex circulating signatures, including the application of machine learning tools and the study of EVs (Heitzer et al, 2019). A growing body of evidence is focusing on the characterization of endothelial EVs isolated from plasma (Igami et al, 2019;Mork et al, 2019;Oliveira et al, 2019;Utermohlen et al, 2019). Even if a consensus on the methods for isolation and characterization of these EVs is far from being reached, it is important to remark that the profiling of the cargo of circulating EVs sorted according to the parent cells allows enhanced specificity compared to single molecular markers in the blood.…”

An estimate of extracellular vesicle secretion rates of human blood cells

“…Mitochondria are a major source of cellular reactive oxygen species (ROS), with mitochondrial Complex I having one of the highest ROS‐generating capacities (Starkov, 2008 ). There is ample evidence that increased cellular ROS levels increase EV secretion; for example, exercise (Wong et al., 2017 ) and hypobaric pressure at higher altitudes (Gaur et al., 2021 ) cause higher plasma EV concentrations (Brahmer et al., 2019 ; Frühbeis et al., 2015 ; Utermöhlen et al., 2019 ; Whitham et al., 2018 ) in healthy humans. Moreover, ultraviolet light generates ROS (de Jager et al., 2017 ) and increase EV secretion (Shen et al., 2020 ), and diseases, such as cancers, display high cellular ROS levels (Perillo et al., 2020 ), and cancer cell‐derived are circulating at high levels in patients (Minciacchi et al., 2015 ; Vitale et al., 2021 ).…”