PMID- 36633375
OWN - NLM
STAT- MEDLINE
DCOM- 20230316
LR  - 20240322
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 601
IP  - 6
DP  - 2023 Mar
TI  - Lifelong exposure to high-altitude hypoxia in humans is associated with improved 
      redox homeostasis and structural-functional adaptations of the neurovascular 
      unit.
PG  - 1095-1120
LID - 10.1113/JP283362 [doi]
AB  - High-altitude (HA) hypoxia may alter the structural-functional integrity of the 
      neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea 
      level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de 
      Pasco (CdP), Peru (HA), against sex-, age- and body mass index-matched healthy 
      highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for 
      serum proteins reflecting NVU integrity, in addition to free radicals and nitric 
      oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with 
      cerebral substrate delivery, dynamic cerebral autoregulation (dCA), 
      cerebrovascular reactivity to carbon dioxide (CVR(CO2) ) and neurovascular 
      coupling (NVC). Psychomotor tests were employed to examine cognitive function. 
      Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red 
      blood cell NO bioavailability, improved anterior and posterior dCA, elevated 
      anterior CVR(CO2) and preserved cerebral substrate delivery, NVC and cognition. 
      In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were 
      consistently lower and cognition comparable to lowlanders following chronic-HA. 
      These findings highlight novel integrated adaptations towards regulation of the 
      NVU in highlanders that may represent a neuroprotective phenotype underpinning 
      successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: 
      High-altitude (HA) hypoxia has the potential to alter the structural-functional 
      integrity of the neurovascular unit (NVU) in humans. For the first time, we 
      examined to what extent chronic and lifelong hypoxia impacts multimodal 
      biomarkers reflecting NVU structure and function in lowlanders and native Andean 
      highlanders. Despite lowlanders presenting with a reduction in systemic 
      oxidative-nitrosative stress and maintained cerebral bioenergetics and 
      cerebrovascular function during chronic hypoxia, there was evidence for increased 
      axonal injury and cognitive impairment. Compared to lowlanders at sea level, 
      highlanders exhibited elevated vascular NO bioavailability, improved dynamic 
      regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate 
      delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders 
      following chronic HA, highlanders presented with lower concentrations of S100B, 
      neurofilament light chain and total tau. These findings highlight novel 
      integrated adaptations towards the regulation of the NVU in highlanders that may 
      represent a neuroprotective phenotype underpinning successful adaptation to the 
      lifelong stress of HA hypoxia.
CI  - (c) 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd 
      on behalf of The Physiological Society.
FAU - Stacey, Benjamin S
AU  - Stacey BS
AUID- ORCID: 0000-0003-1005-7038
AD  - Neurovascular Research Laboratory, Faculty of Life Sciences and Education, 
      University of South Wales, Pontypridd, UK.
FAU - Hoiland, Ryan L
AU  - Hoiland RL
AUID- ORCID: 0000-0002-5657-0059
AD  - Department of Anaesthesiology, Pharmacology and Therapeutics, Vancouver General 
      Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
AD  - Department of Cellular and Physiological Sciences, Faculty of Medicine, 
      University of British Columbia, Vancouver, British Columbia, Canada.
FAU - Caldwell, Hannah G
AU  - Caldwell HG
AUID- ORCID: 0000-0001-6072-7277
AD  - Centre for Heart, Lung and Vascular Health, University of British 
      Columbia-Okanagan Campus, Kelowna, British Columbia, Canada.
FAU - Howe, Connor A
AU  - Howe CA
AUID- ORCID: 0000-0002-1133-2444
AD  - Centre for Heart, Lung and Vascular Health, University of British 
      Columbia-Okanagan Campus, Kelowna, British Columbia, Canada.
FAU - Vermeulen, Tyler
AU  - Vermeulen T
AUID- ORCID: 0000-0002-5776-0460
AD  - Centre for Heart, Lung and Vascular Health, University of British 
      Columbia-Okanagan Campus, Kelowna, British Columbia, Canada.
FAU - Tymko, Michael M
AU  - Tymko MM
AD  - Centre for Heart, Lung and Vascular Health, University of British 
      Columbia-Okanagan Campus, Kelowna, British Columbia, Canada.
AD  - Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Department of Medicine, Faculty of Medicine, University of British Columbia, 
      Vancouver, British Columbia, Canada.
FAU - Vizcardo-Galindo, Gustavo A
AU  - Vizcardo-Galindo GA
AUID- ORCID: 0000-0002-8131-8808
AD  - Laboratorio de Fisiologia Comparada, Departamento de Ciencias Biologicas y 
      Fisiologicas, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano 
      Heredia, Lima 31, Peru.
FAU - Bermudez, Daniella
AU  - Bermudez D
AUID- ORCID: 0000-0001-7879-0485
AD  - Laboratorio de Fisiologia Comparada, Departamento de Ciencias Biologicas y 
      Fisiologicas, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano 
      Heredia, Lima 31, Peru.
FAU - Figueroa-Mujiica, Romulo J
AU  - Figueroa-Mujiica RJ
AUID- ORCID: 0000-0003-1364-350X
AD  - Laboratorio de Fisiologia Comparada, Departamento de Ciencias Biologicas y 
      Fisiologicas, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano 
      Heredia, Lima 31, Peru.
FAU - Gasho, Christopher
AU  - Gasho C
AD  - Division of Pulmonary and Critical Care, Loma Linda University School of 
      Medicine, Loma Linda, CA, USA.
FAU - Tuaillon, Edouard
AU  - Tuaillon E
AD  - Department of Infectious Diseases, University of Montpellier, Montpellier, 
      France.
FAU - Hirtz, Christophe
AU  - Hirtz C
AUID- ORCID: 0000-0002-7313-0629
AD  - LBPC-PPC, Universite de Montpellier, IRMB CHU de Montpellier, INM INSERM, 
      Montpellier, France.
FAU - Lehmann, Sylvain
AU  - Lehmann S
AD  - LBPC-PPC, Universite de Montpellier, IRMB CHU de Montpellier, INM INSERM, 
      Montpellier, France.
FAU - Marchi, Nicola
AU  - Marchi N
AD  - Laboratory of Cerebrovascular and Glia Research, Department of Neuroscience, 
      Institute of Functional Genomics, University of Montpellier, Montpellier, France.
FAU - Tsukamoto, Hayato
AU  - Tsukamoto H
AUID- ORCID: 0000-0001-5512-0497
AD  - Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, 
      Japan.
FAU - Villafuerte, Francisco C
AU  - Villafuerte FC
AUID- ORCID: 0000-0003-0731-8911
AD  - Laboratorio de Fisiologia Comparada, Departamento de Ciencias Biologicas y 
      Fisiologicas, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano 
      Heredia, Lima 31, Peru.
FAU - Ainslie, Philip N
AU  - Ainslie PN
AUID- ORCID: 0000-0001-6560-222X
AD  - Neurovascular Research Laboratory, Faculty of Life Sciences and Education, 
      University of South Wales, Pontypridd, UK.
AD  - Centre for Heart, Lung and Vascular Health, University of British 
      Columbia-Okanagan Campus, Kelowna, British Columbia, Canada.
FAU - Bailey, Damian M
AU  - Bailey DM
AUID- ORCID: 0000-0003-0498-7095
AD  - Neurovascular Research Laboratory, Faculty of Life Sciences and Education, 
      University of South Wales, Pontypridd, UK.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230223
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 142M471B3J (Carbon Dioxide)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Humans
MH  - Male
MH  - *Altitude Sickness
MH  - Carbon Dioxide
MH  - Altitude
MH  - Hypoxia
MH  - Acclimatization/physiology
MH  - Oxidation-Reduction
MH  - Nitric Oxide
MH  - Homeostasis
PMC - PMC10952731
OTO - NOTNLM
OT  - acclimatization
OT  - cerebrovascular function
OT  - cognition
OT  - free radicals
OT  - high altitude
OT  - neurovascular unit
COIS- D.M.B. is Editor-in-Chief of Experimental Physiology, Chair of the Life Sciences 
      Working Group and member of the Human Spaceflight and Exploration Science 
      Advisory Committee to the European Space Agency, Space Exploration Advisory 
      Committee to the UK Space Agency, South East Wales Vascular Network, National 
      Cardiovascular Network and Concussion in Sport Committee for The Department for 
      Digital, Culture, Media & Sport (c/o Medical Research Council). D.M.B. is also 
      affiliated to the companies FloTBI Inc., BrainEx Inc. and OrgEx Inc. focused on 
      the technological development of novel biomarkers of brain injury in humans.
EDAT- 2023/01/13 06:00
MHDA- 2023/03/17 06:00
PMCR- 2023/02/23
CRDT- 2023/01/12 08:33
PHST- 2022/06/01 00:00 [received]
PHST- 2022/12/20 00:00 [accepted]
PHST- 2023/01/13 06:00 [pubmed]
PHST- 2023/03/17 06:00 [medline]
PHST- 2023/01/12 08:33 [entrez]
PHST- 2023/02/23 00:00 [pmc-release]
AID - TJP15416 [pii]
AID - 10.1113/JP283362 [doi]
PST - ppublish
SO  - J Physiol. 2023 Mar;601(6):1095-1120. doi: 10.1113/JP283362. Epub 2023 Feb 23.