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

Benjamin Stacey, Hannah G. Caldwell, Ryan L. Hoiland, Philip Ainslie, Connor A. Howe, Tyler D. Vermeulen, Michael Tymko, Christopher Gasho, Gustavo A. Vizcardo-Galindo, Daniela Bermudez, Francisco C. Villafuerte, Romulo J Figueroa-mujica, Édouard Tuaillon, Christoph Hirtz, Sylvain Lehmann, Nicola Marchi, Hayato Tsukamoto, Damian Bailey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 4,300 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). Serum proteins were examined to reflect NVU integrity and venous blood assayed for 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 plasma and red blood cell NO bioavailability (P = 0.005, d = 1.549 and P = 0.003, d = 1.681), improved anterior and posterior dCA (low frequency Gain: P = 0.029, d = -1.292 and P = 0.017, d = -1.255 respectively), elevated anterior CVRCO2 (P = 0.113, d = -0.852) and preserved cerebral substrate delivery and NVC (all P = >0.100). In highlanders, S100B, neurofilament light-chain and T-tau were consistently lower (P = 0.018, d = -1.244, P = 0.037, d = -1.075 and P = <0.001, d = -3.894, respectively) and cognition comparable (all P = >0.100) 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.
Original languageEnglish
JournalThe Journal of Physiology
Volume00
Issue number00
Early online date12 Jan 2023
Publication statusE-pub ahead of print - 12 Jan 2023

Keywords

  • acclimatization
  • cerebrovascular function
  • cognition
  • free radicals
  • high-altitude
  • neurovascular unit

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