TY - JOUR

T1 - Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit

AU - Stacey, Benjamin S

AU - Hoiland, Ryan L

AU - Caldwell, Hannah Grace

AU - Howe, Connor A

AU - Vermeulen, Tyler

AU - Tymko, Michael M

AU - Vizcardo-Galindo, Gustavo A

AU - Bermudez, Daniella

AU - Figueroa-Mujíica, Rómulo J

AU - Gasho, Christopher

AU - Tuaillon, Edouard

AU - Hirtz, Christophe

AU - Lehmann, Sylvain

AU - Marchi, Nicola

AU - Tsukamoto, Hayato

AU - Villafuerte, Francisco C

AU - Ainslie, Philip N

AU - Bailey, Damian M

N1 - This article is protected by copyright. All rights reserved.

PY - 2023

Y1 - 2023

N2 - 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), Péru (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 (CVRCO2) 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 CVRCO2 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.

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), Péru (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 (CVRCO2) 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 CVRCO2 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.

KW - Faculty of Science

KW - Acclimatization

KW - Cerebrovascular function

KW - Cognition

KW - Free radicals

KW - High-altitude

KW - Neurovascular unit

U2 - 10.1113/JP283362

DO - 10.1113/JP283362

M3 - Journal article

C2 - 36633375

VL - 601

SP - 1095

EP - 1120

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 6

ER -