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Increased endothelial microparticles and oxidative stress at extreme altitude

  • Original Article
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European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

Purpose

Hypoxia and oxidative stress affect endothelial function. Endothelial microparticles (MP) are established measures of endothelial dysfunction and influence vascular reactivity. To evaluate the effects of hypoxia and antioxidant supplementation on endothelial MP profiles, a double-blind, placebo-controlled trial, during a high altitude expedition was performed.

Methods

29 participants were randomly assigned to a treatment group (n = 14), receiving vitamin E, C, A, and N-acetylcysteine daily, and a control group (n = 15), receiving placebo. Blood samples were obtained at 490 m (baseline), 3530, 4590, and 6210 m. A sensitive tandem mass spectrometry method was used to measure 8-iso-prostaglandin F2α and hydroxyoctadecadienoic acids as markers of oxidative stress. Assessment of MP profiles including endothelial activation markers (CD62+MP and CD144+MP) and cell apoptosis markers (phosphatidylserine+MP and CD31+MP) was performed using a standardized flow cytometry-based protocol.

Results

15 subjects reached all altitudes and were included in the final analysis. Oxidative stress increased significantly at altitude. No statistically significant changes were observed comparing baseline to altitude measurements of phosphatidylserine expressing MP (p = 0.1718) and CD31+MP (p = 0.1305). Compared to baseline measurements, a significant increase in CD62+MP (p = 0.0079) and of CD144+MP was detected (p = 0.0315) at high altitudes. No significant difference in any MP level or oxidative stress markers were found between the treatment and the control group.

Conclusion

Hypobaric hypoxia is associated with increased oxidative stress and induces a significant increase in CD62+ and CD144+MP, whereas phosphatidylserine+MP and CD31+MP remain unchanged. This indicates that endothelial activation rather than an apoptosis is the primary factor of hypoxia induced endothelial dysfunction.

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Abbreviations

AMS:

Acute mountain sickness

ANOVA:

Analysis of variance

BH4:

Tetrahydrobiopterin

CD31+MP:

Cluster of differentiation 31 positive microparticle also known as platelet endothelial cell adhesion molecule positive microparticle

CD62+MP:

Cluster of differentiation 62 positive microparticle also known as endothelial-selectin positive microparticle

CD144+MP:

Cluster of differentiation 144 positive microparticle also known as vascular endothelial-cadherin positive microparticle

HACE:

High altitude cerebral edema

HAPE:

High altitude pulmonary edema

HODE:

Hydroxyoctadecadienoic acid

iPF2α-III:

8-Iso-prostaglandin F2α

LLS:

Lake Louise acute mountain sickness score

MP:

Microparticles

NAC:

N-acetylcysteine

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PS:

Phosphatidylserine

PS+MP:

Phosphatidylserine positive microparticle

ROS:

Reactive oxygen species

SpO2 :

Pulse oxymetric arterial oxygen saturation

9-HODE:

(±)9-Hydroxy-10E,12Z-octadecadienoic acid

13-HODE:

13(S)-Hydroxy-9Z,11E-octadecadienoic acid

References

  • Akinnusi ME, El Solh AA (2009) Circulating endothelial microparticle levels and hemodynamic severity of pulmonary hypertension: is there a role for sleep apnea? Am J Respir Crit Care Med 179(4):328

    Article  PubMed  Google Scholar 

  • Amabile N, Heiss C, Real WM, Minasi P, McGlothlin D, Rame EJ, Grossman W, De Marco T, Yeghiazarians Y (2008) Circulating endothelial microparticle levels predict hemodynamic severity of pulmonary hypertension. Am J Respir Crit Care Med 177(11):1268–1275. doi:10.1164/rccm.200710-1458OC

    Article  CAS  PubMed  Google Scholar 

  • Amabile N, Heiss C, Chang V, Angeli FS, Damon L, Rame EJ, McGlothlin D, Grossman W, De Marco T, Yeghiazarians Y (2009) Increased CD62e(+) endothelial microparticle levels predict poor outcome in pulmonary hypertension patients. J Heart Lung Transplant 28(10):1081–1086. doi:10.1016/j.healun.2009.06.005

    Article  PubMed  Google Scholar 

  • Angelini DJ, Hyun SW, Grigoryev DN, Garg P, Gong P, Singh IS, Passaniti A, Hasday JD, Goldblum SE (2006) TNF-alpha increases tyrosine phosphorylation of vascular endothelial cadherin and opens the paracellular pathway through fyn activation in human lung endothelia. Am J Physiol Lung Cell Mol Physiol 291(6):L1232–L1245. doi:10.1152/ajplung.00109.2006

    Article  CAS  PubMed  Google Scholar 

  • Ayers L, Stoewhas AC, Ferry B, Latshang TD, Lo Cascio CM, Sadler R, Stadelmann K, Tesler N, Huber R, Achermann P, Bloch KE, Kohler M (2014) Circulating levels of cell-derived microparticles are reduced by mild hypobaric hypoxia: data from a randomised controlled trial. Eur J Appl Physiol 114(5):1067–1073. doi:10.1007/s00421-014-2837-6

    Article  CAS  PubMed  Google Scholar 

  • Bailey DM, Davies B (2001) Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude. High Alt Med Biol 2(1):21–29. doi:10.1089/152702901750067882

    Article  CAS  PubMed  Google Scholar 

  • Bailey DM, Roukens R, Knauth M, Kallenberg K, Christ S, Mohr A, Genius J, Storch-Hagenlocher B, Meisel F, McEneny J, Young IS, Steiner T, Hess K, Bartsch P (2006) Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache. J Cereb Blood Flow Metab 26(1):99–111. doi:10.1038/sj.jcbfm.9600169

    Article  CAS  PubMed  Google Scholar 

  • Bailey DM, Evans KA, James PE, McEneny J, Young IS, Fall L, Gutowski M, Kewley E, McCord JM, Moller K, Ainslie PN (2009) Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function. J Physiol 587(Pt 1):73–85. doi:10.1113/jphysiol.2008.159855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey DM, Dehnert C, Luks AM, Menold E, Castell C, Schendler G, Faoro V, Gutowski M, Evans KA, Taudorf S, James PE, McEneny J, Young IS, Swenson ER, Mairbaurl H, Bartsch P, Berger MM (2010) High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability. J Physiol 588(Pt 23):4837–4847. doi:10.1113/jphysiol.2010.194704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baillie JK, Thompson AA, Irving JB, Bates MG, Sutherland AI, Macnee W, Maxwell SR, Webb DJ (2009) Oral antioxidant supplementation does not prevent acute mountain sickness: double blind, randomized placebo-controlled trial. QJM Mon J Assoc Phys 102(5):341–348. doi:10.1093/qjmed/hcp026

    CAS  Google Scholar 

  • Bakouboula B, Morel O, Faure A, Zobairi F, Jesel L, Trinh A, Zupan M, Canuet M, Grunebaum L, Brunette A, Desprez D, Chabot F, Weitzenblum E, Freyssinet JM, Chaouat A, Toti F (2008) Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. Am J Respir Crit Care Med 177(5):536–543. doi:10.1164/rccm.200706-840OC

    Article  CAS  PubMed  Google Scholar 

  • Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE (2005) Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med 172(6):763–767. doi:10.1164/rccm.200504-654OC

    Article  PubMed  Google Scholar 

  • Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2012) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 3:CD007176. doi:10.1002/14651858.CD007176.pub2

  • Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS (2000) Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 356(9237):1213–1218

    Article  CAS  PubMed  Google Scholar 

  • Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, Tedgui A, Mallat Z (2001) Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104(22):2649–2652

    Article  CAS  PubMed  Google Scholar 

  • Boulanger CM, Amabile N, Guerin AP, Pannier B, Leroyer AS, Mallat CN, Tedgui A, London GM (2007) In vivo shear stress determines circulating levels of endothelial microparticles in end-stage renal disease. Hypertension 49(4):902–908. doi:10.1161/01.HYP.0000259667.22309.df

    Article  CAS  PubMed  Google Scholar 

  • Budhiraja R, Tuder RM, Hassoun PM (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109(2):159–165. doi:10.1161/01.CIR.0000102381.57477.50

    Article  PubMed  Google Scholar 

  • Bull TM, Golpon H, Hebbel RP, Solovey A, Cool CD, Tuder RM, Geraci MW, Voelkel NF (2003) Circulating endothelial cells in pulmonary hypertension. Thromb Haemost 90(4):698–703. doi:10.1267/THRO03040698

    CAS  PubMed  Google Scholar 

  • Burhop KE, Selig WM, Malik AB (1988) Monohydroxyeicosatetraenoic acids (5-HETE and 15-HETE) induce pulmonary vasoconstriction and edema. Circ Res 62(4):687–698

    Article  CAS  PubMed  Google Scholar 

  • Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95(20):11715–11720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandler WL, Yeung W, Tait JF (2011) A new microparticle size calibration standard for use in measuring smaller microparticles using a new flow cytometer. J Thromb Haemost 9(6):1216–1224. doi:10.1111/j.1538-7836.2011.04283.x

    Article  CAS  PubMed  Google Scholar 

  • Chao WH, Askew EW, Roberts DE, Wood SM, Perkins JB (1999) Oxidative stress in humans during work at moderate altitude. J Nutr 129(11):2009–2012

    CAS  PubMed  Google Scholar 

  • Chaumais MC, Ranchoux B, Montani D, Dorfmuller P, Tu L, Lecerf F, Raymond N, Guignabert C, Price L, Simonneau G, Cohen-Kaminsky S, Humbert M, Perros F (2014) N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats. Respir Res 15:65. doi:10.1186/1465-9921-15-65

    Article  PubMed  PubMed Central  Google Scholar 

  • Chichger H, Duong H, Braza J, Harrington EO (2014) p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE-cadherin. FASEB J Off Publ Fed Am Soc Exp Biol. doi:10.1096/fj.14-257212

    Google Scholar 

  • Connolly MJ, Aaronson PI (2010) Cell redox state and hypoxic pulmonary vasoconstriction: recent evidence and possible mechanisms. Respir Physiol Neurobiol 174(3):165–174. doi:10.1016/j.resp.2010.08.016

    Article  CAS  PubMed  Google Scholar 

  • Corada M, Liao F, Lindgren M, Lampugnani MG, Breviario F, Frank R, Muller WA, Hicklin DJ, Bohlen P, Dejana E (2001) Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability. Blood 97(6):1679–1684

    Article  CAS  PubMed  Google Scholar 

  • Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115(10):1285–1295. doi:10.1161/circulationaha.106.652859

    PubMed  Google Scholar 

  • Delannoy E, Courtois A, Freund-Michel V, Leblais V, Marthan R, Muller B (2010) Hypoxia-induced hyperreactivity of pulmonary arteries: role of cyclooxygenase-2, isoprostanes, and thromboxane receptors. Cardiovasc Res 85(3):582–592. doi:10.1093/cvr/cvp292

    Article  CAS  PubMed  Google Scholar 

  • Delanty N, Reilly M, Pratico D, FitzGerald DJ, Lawson JA, FitzGerald GA (1996) 8-Epi PGF2 alpha: specific analysis of an isoeicosanoid as an index of oxidant stress in vivo. Br J Clin Pharmacol 42(1):15–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dosek A, Ohno H, Acs Z, Taylor AW, Radak Z (2007) High altitude and oxidative stress. Respir Physiol Neurobiol 158(2–3):128–131. doi:10.1016/j.resp.2007.03.013

    Article  CAS  PubMed  Google Scholar 

  • Fike CD, Kaplowitz MR, Pfister SL (2003) Arachidonic acid metabolites and an early stage of pulmonary hypertension in chronically hypoxic newborn pigs. Am J Physiol Lung Cell Mol Physiol 284(2):L316–L323. doi:10.1152/ajplung.00228.2002

    Article  CAS  PubMed  Google Scholar 

  • Herren B, Levkau B, Raines EW, Ross R (1998) Cleavage of beta-catenin and plakoglobin and shedding of VE-cadherin during endothelial apoptosis: evidence for a role for caspases and metalloproteinases. Mol Biol Cell 9(6):1589–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hjuler Nielsen M, Irvine H, Vedel S, Raungaard B, Beck-Nielsen H, Handberg A (2015) Elevated atherosclerosis-related gene expression, monocyte activation and microparticle-release are related to increased lipoprotein-associated oxidative stress in familial hypercholesterolemia. PLoS One 10(4):e0121516. doi:10.1371/journal.pone.0121516

    Article  PubMed  PubMed Central  Google Scholar 

  • Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, Spitsin SV (2000) Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J Off Publ Fed Am Soc Exp Biol 14(5):691–698

    CAS  Google Scholar 

  • Horigome H, Hiramatsu Y, Shigeta O, Nagasawa T, Matsui A (2002) Overproduction of platelet microparticles in cyanotic congenital heart disease with polycythemia. J Am Coll Cardiol 39(6):1072–1077

    Article  PubMed  Google Scholar 

  • Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, Noda M, Tabata T, Voelkel NF, Fujimura S (2001) Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol (1985) 90(4):1299–1306

    CAS  Google Scholar 

  • Hoyos B, Acin-Perez R, Fischman DA, Manfredi G, Hammerling U (2012) Hiding in plain sight: uncovering a new function of vitamin A in redox signaling. Biochim Biophys Acta 1821 1:241–247. doi:10.1016/j.bbalip.2011.06.014

    Article  Google Scholar 

  • Ihlemann N, Rask-Madsen C, Perner A, Dominguez H, Hermann T, Kober L, Torp-Pedersen C (2003) Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am J Physiol Heart Circ Physiol 285(2):H875–H882. doi:10.1152/ajpheart.00008.2003

    Article  CAS  PubMed  Google Scholar 

  • Jimenez JJ, Jy W, Mauro LM, Soderland C, Horstman LL, Ahn YS (2003) Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb Res 109(4):175–180

    Article  CAS  PubMed  Google Scholar 

  • Kuiper HC, Bruno RS, Traber MG, Stevens JF (2011) Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Radic Biol Med 50(7):848–853. doi:10.1016/j.freeradbiomed.2011.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis NC, Bailey DM, Dumanoir GR, Messinger L, Lucas SJ, Cotter JD, Donnelly J, McEneny J, Young IS, Stembridge M, Burgess KR, Basnet AS, Ainslie PN (2014) Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation. J Physiol 592(Pt 5):1009–1024. doi:10.1113/jphysiol.2013.268615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lichtenauer M, Goebel B, Fritzenwanger M, Forster M, Betge S, Lauten A, Figulla HR, Jung C (2014) Simulated temporary hypoxia triggers the release of CD31+/Annexin + endothelial microparticles: a prospective pilot study in humans. Clin Hemorheol Microcirc. doi:10.3233/CH-141908

    Google Scholar 

  • Lynch SF, Ludlam CA (2007) Plasma microparticles and vascular disorders. Br J Haematol 137(1):36–48. doi:10.1111/j.1365-2141.2007.06514.x

    CAS  PubMed  Google Scholar 

  • Maggiorini M, Melot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U, Naeije R (2001) High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 103(16):2078–2083

    Article  CAS  PubMed  Google Scholar 

  • Marcos-Ramiro B, Oliva Nacarino P, Serrano-Pertierra E, Blanco-Gelaz MA, Weksler BB, Romero IA, Couraud PO, Tunon A, Lopez-Larrea C, Millan J, Cernuda-Morollon E (2014) Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neurosci 15:110. doi:10.1186/1471-2202-15-110

    Article  PubMed  PubMed Central  Google Scholar 

  • Mastronardi ML, Mostefai HA, Meziani F, Martinez MC, Asfar P, Andriantsitohaina R (2011) Circulating microparticles from septic shock patients exert differential tissue expression of enzymes related to inflammation and oxidative stress. Crit Care Med 39(7):1739–1748. doi:10.1097/CCM.0b013e3182190b4b

    Article  CAS  PubMed  Google Scholar 

  • Milne GL, Yin H, Brooks JD, Sanchez S, Jackson Roberts L 2nd, Morrow JD (2007) Quantification of F2-isoprostanes in biological fluids and tissues as a measure of oxidant stress. Methods Enzymol 433:113–126. doi:10.1016/S0076-6879(07)33006-1

    Article  CAS  PubMed  Google Scholar 

  • Montezano AC, Dulak-Lis M, Tsiropoulou S, Harvey A, Briones AM, Touyz RM (2015) Oxidative stress and human hypertension: vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol 31(5):631–641. doi:10.1016/j.cjca.2015.02.008

    Article  PubMed  Google Scholar 

  • Montoro-Garcia S, Shantsila E, Marin F, Blann A, Lip GY (2011) Circulating microparticles: new insights into the biochemical basis of microparticle release and activity. Basic Res Cardiol. doi:10.1007/s00395-011-0198-4

    PubMed  Google Scholar 

  • Montuschi P, Barnes PJ, Roberts LJ 2nd (2004) Isoprostanes: markers and mediators of oxidative stress. FASEB J Off Publ Fed Am Soc Exp Biol 18(15):1791–1800. doi:10.1096/fj.04-2330rev

    CAS  Google Scholar 

  • Nunes GL, Robinson K, Kalynych A, King SB 3rd, Sgoutas DS, Berk BC (1997) Vitamins C and E inhibit O2-production in the pig coronary artery. Circulation 96(10):3593–3601

    Article  CAS  PubMed  Google Scholar 

  • Palace VP, Hill MF, Khaper N, Singal PK (1999) Metabolism of vitamin A in the heart increases after a myocardial infarction. Free Radic Biol Med 26(11–12):1501–1507

    Article  CAS  PubMed  Google Scholar 

  • Pichler Hefti J, Risch L, Hefti U, Scharrer I, Risch G, Merz TM, Turk A, Bosch MM, Barthelmess D, Schoch O, Maggiorini M, Huber AR (2010) Changes of coagulation parameters during high altitude expedition. Swiss Med Wkly 140(7–8):111–117

    PubMed  Google Scholar 

  • Pichler Hefti J, Sonntag D, Hefti U, Risch L, Schoch OD, Turk AJ, Hess T, Bloch KE, Maggiorini M, Merz TM, Weinberger KM, Huber AR (2013) Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators. High Alt Med Biol 14(3):273–279. doi:10.1089/ham.2012.1110

    Article  CAS  PubMed  Google Scholar 

  • Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA (1998) Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med 4(10):1189–1192. doi:10.1038/2685

    Article  CAS  PubMed  Google Scholar 

  • Roach RC, Bartsch P, Hackett PH, Oelz O (1993) Hypoxia and molecular medicine. In: The Lake Louise acute mountain sickness scoring system. Suton JR, Coates G, Houston Ch, Burlington

  • Schmidt MC, Askew EW, Roberts DE, Prior RL, Ensign WY Jr, Hesslink RE Jr (2002) Oxidative stress in humans training in a cold, moderate altitude environment and their response to a phytochemical antioxidant supplement. Wilderness Environ Med 13(2):94–105

    Article  PubMed  Google Scholar 

  • Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5(5):343–354. doi:10.1038/nrm1366

    Article  CAS  PubMed  Google Scholar 

  • Schulz B, Pruessmeyer J, Maretzky T, Ludwig A, Blobel CP, Saftig P, Reiss K (2008) ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. Circ Res 102(10):1192–1201. doi:10.1161/CIRCRESAHA.107.169805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sidibe A, Imhof BA (2014) VE-cadherin phosphorylation decides: vascular permeability or diapedesis. Nat Immunol 15(3):215–217. doi:10.1038/ni.2825

    Article  CAS  PubMed  Google Scholar 

  • Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ (1996) Randomised controlled trial of vitamin E in patients with coronary disease: cambridge Heart Antioxidant Study (CHAOS). Lancet 347(9004):781–786

    Article  CAS  PubMed  Google Scholar 

  • Thiagarajan P, Tait JF (1991) Collagen-induced exposure of anionic phospholipid in platelets and platelet-derived microparticles. J Biol Chem 266(36):24302–24307

    CAS  PubMed  Google Scholar 

  • Toth B, Nikolajek K, Rank A, Nieuwland R, Lohse P, Pihusch V, Friese K, Thaler CJ (2007) Gender-specific and menstrual cycle dependent differences in circulating microparticles. Platelets 18(7):515–521. doi:10.1080/09537100701525843

    Article  CAS  PubMed  Google Scholar 

  • Traber MG, Stevens JF (2011) Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med 51(5):1000–1013. doi:10.1016/j.freeradbiomed.2011.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsimerman G, Roguin A, Bachar A, Melamed E, Brenner B, Aharon A (2011) Involvement of microparticles in diabetic vascular complications. Thromb Haemost. doi:10.1160/TH10-11-0712

    PubMed  Google Scholar 

  • Tual-Chalot S, Guibert C, Muller B, Savineau JP, Andriantsitohaina R, Martinez MC (2010) Circulating microparticles from pulmonary hypertensive rats induce endothelial dysfunction. Am J Respir Crit Care Med 182(2):261–268. doi:10.1164/rccm.200909-1347OC

    Article  CAS  PubMed  Google Scholar 

  • Tushuizen ME, Nieuwland R, Scheffer PG, Sturk A, Heine RJ, Diamant M (2006) Two consecutive high-fat meals affect endothelial-dependent vasodilation, oxidative stress and cellular microparticles in healthy men. J Thromb Haemost 4(5):1003–1010. doi:10.1111/j.1538-7836.2006.01914.x

    Article  CAS  PubMed  Google Scholar 

  • Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437(7057):426–431. doi:10.1038/nature03952

    Article  CAS  PubMed  Google Scholar 

  • van der Pol E, van Gemert MJ, Sturk A, Nieuwland R, van Leeuwen TG (2012) Single vs swarm detection of microparticles and exosomes by flow cytometry. J Thromb Haemost JTH 10(5):919–930. doi:10.1111/j.1538-7836.2012.04683.x

    Article  PubMed  Google Scholar 

  • VanWijk MJ, VanBavel E, Sturk A, Nieuwland R (2003) Microparticles in cardiovascular diseases. Cardiovasc Res 59(2):277–287

    Article  CAS  PubMed  Google Scholar 

  • Vasquez-Vivar J, Hogg N, Martasek P, Karoui H, Pritchard KA Jr, Kalyanaraman B (1999) Tetrahydrobiopterin-dependent inhibition of superoxide generation from neuronal nitric oxide synthase. J Biol Chem 274(38):26736–26742

    Article  CAS  PubMed  Google Scholar 

  • Vion AC, Ramkhelawon B, Loyer X, Chironi G, Devue C, Loirand G, Tedgui A, Lehoux S, Boulanger CM (2013) Shear stress regulates endothelial microparticle release. Circ Res 112(10):1323–1333. doi:10.1161/CIRCRESAHA.112.300818

    Article  CAS  PubMed  Google Scholar 

  • Wallez Y, Huber P (2008) Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochim Biophys Acta 1778(3):794–809. doi:10.1016/j.bbamem.2007.09.003

    Article  CAS  PubMed  Google Scholar 

  • Werner N, Wassmann S, Ahlers P, Kosiol S, Nickenig G (2006) Circulating CD31+/annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 26(1):112–116. doi:10.1161/01.ATV.0000191634.13057.15

    Article  CAS  PubMed  Google Scholar 

  • Westerterp-Plantenga MS, Westerterp KR, Rubbens M, Verwegen CR, Richelet JP, Gardette B (1999) Appetite at “high altitude” [Operation Everest III (Comex-’97)]: a simulated ascent of Mount Everest. J Appl Physiol (1985) 87(1):391–399

    CAS  Google Scholar 

  • Wingler K, Wunsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH (2001) Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. Free Radic Biol Med 31(11):1456–1464

    Article  CAS  PubMed  Google Scholar 

  • Wohlfart P, Xu H, Endlich A, Habermeier A, Closs EI, Hubschle T, Mang C, Strobel H, Suzuki T, Kleinert H, Forstermann U, Ruetten H, Li H (2008) Antiatherosclerotic effects of small-molecular-weight compounds enhancing endothelial nitric-oxide synthase (eNOS) expression and preventing eNOS uncoupling. J Pharmacol Exp Ther 325(2):370–379. doi:10.1124/jpet.107.128009

    Article  CAS  PubMed  Google Scholar 

  • Wray DW, Nishiyama SK, Harris RA, Zhao J, McDaniel J, Fjeldstad AS, Witman MA, Ives SJ, Barrett-O’Keefe Z, Richardson RS (2012) Acute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension 59(4):818–824. doi:10.1161/HYPERTENSIONAHA.111.189456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida Y, Niki E (2006) Bio-markers of lipid peroxidation in vivo: hydroxyoctadecadienoic acid and hydroxycholesterol. BioFactors 27(1–4):195–202

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Li T, Liu X, Yu H, Hao Z, Chen Y, Zhang C, Liu Y, Li Q, Mao M, Zhu D (2015) Modulation of pulmonary vascular remodeling in hypoxia: role of 15-LOX-2/15-HETE-MAPKs pathway. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 35(6):2079–2097. doi:10.1159/000374015

    Article  CAS  Google Scholar 

  • Yuan SY (2002) Protein kinase signaling in the modulation of microvascular permeability. Vascul Pharmacol 39(4–5):213–223

    Article  CAS  PubMed  Google Scholar 

  • Zwaal RF, Schroit AJ (1997) Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 89(4):1121–1132

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank all the volunteers, mountain guides, and local staff for their invaluable support of this research project. Equipment was kindly provided by Hettich AG, Bäch, Switzerland. This study was supported by the Swiss Society of Mountain Medicine.

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Authors and Affiliations

  1. Department of Pneumology, University Hospital and University of Bern, Bern, Switzerland

    Jacqueline Pichler Hefti & Thomas Geiser

  2. Department of Intensive Care Medicine, University Hospital and University of Bern, Bern, Switzerland

    Jacqueline Pichler Hefti & Tobias M. Merz

  3. University Institute of Clinical Chemistry, University Hospital and University of Bern, Bern, Switzerland

    Alexander Leichtle

  4. Department of Clinical Investigation, University Hospital and University of Bern, Bern, Switzerland

    Monika Stutz

  5. Swiss Sportsclinic, Bern, Switzerland

    Urs Hefti

  6. Center of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland

    Andreas R. Huber

Authors
  1. Jacqueline Pichler Hefti
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  2. Alexander Leichtle
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  3. Monika Stutz
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  4. Urs Hefti
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  5. Thomas Geiser
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  6. Andreas R. Huber
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  7. Tobias M. Merz
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Corresponding author

Correspondence to Jacqueline Pichler Hefti.

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Communicated by Fabio Fischetti.

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Pichler Hefti, J., Leichtle, A., Stutz, M. et al. Increased endothelial microparticles and oxidative stress at extreme altitude. Eur J Appl Physiol 116, 739–748 (2016). https://doi.org/10.1007/s00421-015-3309-3

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  • DOI: https://doi.org/10.1007/s00421-015-3309-3

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