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

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

Physiology 2023 (Harrogate, UK) (2023) Proc Physiol Soc 54, PCB063

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

Benjamin Stacey1, Ryan Hoiland1, Hannah Caldwell1, Connor Howe1, Tyler Vermeulen1, Michael Tymko1, Gustavo Vizcardo-Galindo1, Daniella Bermudez1, Rómulo Figueroa-MujÃ

1Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales Pontypridd United Kingdom, 2Department of Anaesthesiology, Pharmacology and Therapeutics, Vancouver General Hospital, West 12th Avenue, University of British Columbia Vancouver Canada, 3Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia Vancouver Canada, 4Centre for Heart, Lung and Vascular Health, University of British Columbia-Okanagan Campus, School of Health and Exercise Sciences Kelwona Canada, 5Faculty of Kinesiology, Sport, & Recreation, University of Alberta Edmonton Canada, 6Department of Medicine, Faculty of Medicine, University of British Columbia Vancouver Canada, 7Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia Lima Peru, 8Division of Pulmonary and Critical Care, Loma Linda University School of Medicine, Loma Linda, CA United States, 9Department of Infectious Diseases, University of Montpellier, INSERM Montpellier France, 10University of Montpellier, CHU of Montpellier, INSERM Montpellier France, 11Laboratory of Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics, University of Montpellier Montpellier France, 12Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga Japan,

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Background: The neurovascular unit (NVU) is a functionally integrated cellular network responsible for maintaining structural integrity of the blood-brain barrier (BBB) and regulation of cerebral blood flow (CBF) via neurovascular coupling (NVC). Upon exposure to high-altitude (HA) in lowlanders born and bred at sea-level (SL), BBB integrity may become compromised due to autoregulatory breakthrough subsequent to local elevations in oxidative-nitrosative stress (OXNOS) reflected by a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability (Bailey et al., 2009a; 2009b). Furthermore, MRI evidence of extracellular (vasogenic) edematous brain swelling (Kallenberg et al., 2007) combined with hemosiderin deposits (Kallenberg et al., 2008) implying erythrocyte extravasation, have been collectively interpreted to reflect BBB disruption (Bailey et al., 2009a), predisposing to impaired cerebral bioenergetic function and cognitive decline (Bailey et al., 2019). The aim of the present study was to determine how the hypoxia of HA across the temporal continuum of chronic through to lifelong exposure impacts the NVU phenotype and to what extent this is subject to altered redox homeostasis.

Methods: Nine male lowlanders were examined at SL (~344m) and after 14-days acclimatisation to 4,300 m (chronic HA) in Cerro de Pasco (CdP), Péru, alongside nine sex, age and body mass index-matched healthy highlanders native to CdP (lifelong-HA). Venous blood was assayed for serum proteins (S100B, neuron specific enolase [NSE], glial fibrillary acidic protein [GFAP], neurofilament light-chain [NFL], ubiquitin carboxy-terminal hydrolase-L1 [UCHL-1] and Total-tau [T-Tau]), reflecting NVU integrity via automated high-sensitivity clinical grade ELISA and single molecule array (Simoa) technology. Free radicals and NO were determined using electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence, respectively. Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA, transfer function analysis of spontaneous oscillations of middle/posterior cerebral artery blood velocity [MCAV/PCAV] and mean arterial blood pressure [MAP]), cerebrovascular reactivity to carbon dioxide (CVRCO2, +9 mmHg end-tidal partial pressure of carbon dioxide) and NVC (PCAV responses to visual stimulation) using Transcranial doppler (MCAV/PCAV) and Duplex ultrasound (internal carotid/vertebral artery blood flow: ICAQ/VAQ). Global cerebral blood flow (gCBF) was calculated as (ICAQ  + VAQ) × 2, and substrate (oxygen/glucose) delivery as: gCBF × arterial oxygen content/glucose. Psychomotor tests and the Montreal Cognitive Assessment (MoCA) were employed to examine cognitive function.

Results: Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability (P = 0.003 and P = 0.026, respectively), improved anterior and posterior dCA (↓MCA and PCA LF Gain, P = 0.029 and P = 0.017, respectively), elevated anterior CVRCO2 (↑MCA and ICA CVRCO2, P = 0.036 and P = 0.042, respectively), preserved cerebral substrate delivery and NVC (all P = >0.050). In highlanders, S100B, NFL and T-tau were consistently lower (P = 0.018, P = 0.037 and P = <0.001, respectively) and cognition comparable all (P = >0.050) to lowlanders following chronic-HA.

Conclusions: 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.

Where applicable, experiments conform with Society ethical requirements.

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