The impact of hypoxaemia on vascular function in lowlanders and high altitude indigenous populations

Abstract

Exposure to hypoxia elicits widespread physiological responses that are critical for successful acclimatization; however, these responses may induce apparent maladaptive consequences. For example, recent studies conducted in both the laboratory and the field (e.g. at high altitude) have demonstrated that endothelial function is reduced in hypoxia. Herein, we review the several proposed mechanism(s) pertaining to the observed reduction in endothelial function in hypoxia including: (i) changes in blood flow patterns (i.e. shear stress), (ii) increased inflammation and production of reactive oxygen species (i.e. oxidative stress), (iii) heightened sympathetic nerve activity, and (iv) increased red blood cell concentration and mass leading to elevated nitric oxide scavenging. Although some of these mechanism(s) have been examined in lowlanders, less in known about endothelial function in indigenous populations that have chronically adapted to environmental hypoxia for millennia (e.g. the Peruvian, Tibetan and Ethiopian highlanders). There is some evidence indicating that healthy Tibetan and Peruvian (i.e. Andean) highlanders have preserved endothelial function at high altitude, but less is known about the Ethiopian highlanders. However, Andean highlanders suffering from chronic mountain sickness, which is characterized by an excessive production of red blood cells, have markedly reduced endothelial function. This review will provide a framework and mechanistic model for vascular endothelial adaptation to hypoxia in lowlanders and highlanders. Elucidating the pathways responsible for vascular adaption/maladaptation to hypoxia has potential clinical implications for disease featuring low oxygen delivery (e.g. heart failure, pulmonary disease). In addition, a greater understanding of vascular function at high altitude will clinically benefit the global estimated 85 million high altitude residents.

Global REACH 2018: The carotid artery diameter response to the cold pressor test is governed by arterial blood pressure during normoxic but not hypoxic conditions in healthy lowlanders and Andean highlanders

“…These data indicate that the CCA diameter response to the CPT might not accurately represent vascular ‘health’ at high altitude, because other established methods of vascular function, such as brachial artery flow‐mediated dilatation (Tremblay et al., 2018) or the forearm vascular response to acetylcholine (Tymko et al., 2020b), have demonstrated that vascular function is reduced at high altitude >4000 m a.s.l. in healthy lowlanders (also reviewed by Tymko et al., 2019). Alternatively, given that flow‐mediated dilatation is primarily mediated by endothelial function (Green, Jones, Thijssen, Cable, & Atkinson, 2011), whereas the present data indicate that the CCA diameter response is.…”

“…hypobaric hypoxia) exposure on vascular health. Owing to long‐term adaptation, previous studies conducted in healthy Andean and Sherpa highlanders born at high altitude indicate that these populations have improved vascular health compared with acclimatized lowlanders, which might facilitate improved convective oxygen delivery (Rimoldi et al., 2012; Tremblay et al., 2018; Tymko, Tremblay, Bailey, Green, & Ainslie, 2019). In the context of the assessment of vascular function, the CPT is a simple, non‐invasive test that can potentially give insight into the impact of high altitude on vascular function in health.…”

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…In the mitochondrial matrix, superoxide dismutase (SOD) 2 reduces O 2 − into H 2 O 2 , a less toxic ROS [83]. Then, glutathione peroxidase (GPX) catalyzes the reduction of H 2 O 2 into H 2 O through the oxidation of reduced glutathione (GSH) into its oxidized form (GSSG) [84,85].…”

Involvement of overweight and lipid metabolism in the development of pulmonary hypertension under conditions of chronic intermittent hypoxia

“…21%), the partial pressure of inspired oxygen (PO 2 ) and the saturation of arterial hemoglobin (SaO 2 ) decrease. 2 The latter generates changes in the oxygen transport cascade from ambient air to cellular mitochondria. 3 At an altitude above 2000 m, humans may begin to suffer from high-altitude illnesses.…”

“…∼21%), the partial pressure of inspired oxygen (PO 2 ) and the saturation of arterial hemoglobin (SaO 2 ) decrease. 2 …”