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Patrician, Alexander M. D.

University of British Columbia

With ascent to high altitude, the reduction in the partial pressure of oxygen (PO₂) drives the stabilization of the hypoxia-inducible factor (HIF) family. As the key cellular oxygen sensor, HIF up-regulates the expression of numerous genes designed to increase and preserve O₂ tissue delivery. Since iron plays an inverse and constituent role in HIF stabilization, the overall objectives of the current thesis were: 1) determine the role of iron status manipulation on pulmonary, peripheral and cerebral responses to high-altitude; 2) and examine if indigenous high-altitude populations (i.e. Sherpa and Andeans), with ancestral adaptation to their hypoxic environment, exhibit iron-regulatory advantages. Study 1 investigated the effects of ascent and prolonged stay at 5050 m on iron status and hypoxic pulmonary vasoconstriction. The primary findings were that 1) during ascent, reductions in iron bioavailability were more prevalent in lowlanders, compared to Sherpa; 2) following partial acclimatization to 5050 m, iron infusion (HIF-down regulation) attenuated pulmonary artery systolic pressure (PASP) in both lowlanders and Sherpa while deferoxamine infusion (HIF-up regulation) had little influence. Study 2, in a block-randomized and placebo-controlled design, examined whether the pulmonary vasculature of lowlanders and adapted Andeans at 4300 m are responsive to iron infusion. The findings revealed that, unlike the placebo condition, iron infusion reduced PASP in both lowlanders and Andeans. Study 3 then evaluated the role of iron infusion on peripheral vascular function in the same volunteers at 4300 m. Here, iron infusion (but not saline) increased brachial blood flow and increased microvascular function across the 4-hours, in both lowlanders and Andeans. Upon pooling data (n=83), across both lowlanders and highlanders, Study 4 explored whether the same iron manipulations can modulate hypoxic cerebral vasodilation. It was found that baseline iron levels were related to the variability in magnitude of the hypoxic cerebral vasodilation at high-altitude. In summary, new evidence is provided that support iron status may influence blood flow regulation in the pulmonary, peripheral and cerebral circulations during exposure to high-altitude. Future studies are needed to explore the mechanisms and implications of these observations in high-altitude physiology and pathology.

Text

2022-04-06

Attribution-NonCommercial-ShareAlike 4.0 International

http://hdl.handle.net/2429/81101

Interdisciplinary Studies

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-sa/4.0/