Pulmonary hypertension is attenuated and ventilation-perfusion matching is maintained during chronic hypoxia in deer mice native to high altitude

Abstract

Hypoxia at high altitude can constrain metabolism and performance, and can elicit physiological adjustments that are deleterious to health and fitness. Hypoxic pulmonary hypertension is a particularly serious and maladaptive response to chronic hypoxia, which results from vasoconstriction and pathological remodeling of pulmonary arteries, and can lead to pulmonary edema and right ventricle hypertrophy. We investigated whether deer mice (Peromyscus maniculatus) native to high altitude have attenuated this maladaptive response to chronic hypoxia, and whether evolved changes or hypoxia-induced plasticity in pulmonary vasculature might impact ventilation-perfusion (V-Q) matching in chronic hypoxia. Deer mouse populations from both high and low altitudes were born and raised to adulthood in captivity at sea level, and various aspects of lung function were measured before and after exposure to chronic hypoxia (12 kPa O2, simulating the O2 pressure at 4300 m) for 6-8 weeks. In lowlanders, chronic hypoxia increased right ventricle systolic pressure (RVSP) from 14 to 19 mmHg (P = 0.001), in association with thickening of smooth muscle in pulmonary arteries and right ventricle hypertrophy. Chronic hypoxia also impaired V-Q matching in lowlanders (measured at rest using SPECT-CT imaging), as reflected by increased log SD of the perfusion distribution (log SDQ) from 0.55 to 0.86 (P = 0.031). In highlanders, chronic hypoxia had attenuated effects on RVSP and no effects on smooth muscle thickness, right ventricle mass, or V-Q matching. Therefore, evolved changes in lung function help attenuate maladaptive plasticity and contribute to hypoxia tolerance in high-altitude deer mice.

Distinct Mechanisms Underlie Developmental Plasticity and Adult Acclimation of Thermogenic Capacity in High-Altitude Deer Mice

“…The increases in pulmonary ventilation and volumes induced by developmental hypoxia likely interact with evolved and acclimation-induced variation in other traits across the O 2 transport pathway in high-altitude deer mice. Our findings here are consistent with previous observations that highlanders exhibit higher arterial O 2 saturation at V̇O 2max than lowlanders, which likely arise from population differences in pulmonary function and hemoglobin-O 2 affinity ( Snyder et al, 1982 ; Storz et al, 2009 , 2010a ; Ivy et al, 2020 ; Tate et al, 2020 ; West et al, 2021a , b ). Developmental hypoxia increases hemoglobin-O 2 affinity starting at P14–P30 ( Ivy and Scott, 2021 ), and if this effect persists into adulthood then it might have contributed to some of the plasticity in arterial O 2 saturation observed here.…”

“…Some other observed effects of hypoxia could represent maladaptive plasticity. Our finding that lowland white-footed mice exhibit right-ventricle hypertrophy in response to hypoxia acclimation in adulthood is consistent with recent findings in low-altitude deer mice and white-footed mice (Velotta et al, 2018;West et al, 2021b) along with many other lowland taxa (Monge-C et al, 1992;Zungu et al, 2008;Jochmans-Lemoine et al, 2015). This likely represents a pathological outcome of hypoxic pulmonary hypertension (HPH), a maladaptive response to chronic hypoxia that contributes to disease in humans (e.g., mountain sickness) and other mammals (e.g., brisket disease in cattle; Monge-C et al, 1992;Rhodes, 2005).…”

“…We also found that parental hypoxia exposure in lowlanders led to right-ventricle hypertrophy in offspring that were never exposed to hypoxia themselves. In contrast, in high-altitude deer mice, HPH is attenuated and right-ventricle hypertrophy does not occur during hypoxia exposure in adulthood ( Velotta et al, 2018 ; West et al, 2021b ), and parental hypoxia does not lead to persistent effects on the right ventricle. The difference between high-altitude deer mice and white-footed mice in the effects of chronic hypoxia in adulthood on right-ventricle mass is associated with appreciable differences in right-ventricle gene expression ( Velotta et al, 2018 ).…”

Adrenergic control of the cardiovascular system in deer mice native to high altitude

“…As a result of selection, high-altitude deer mice have evolved increased thermogenic V O 2 max in hypoxia compared to low-altitude populations of deer mice and to white-footed mice, a congeneric species that is restricted to low altitudes ( Chappell et al, 1988 ; Chappell and Snyder, 1984 ; Cheviron et al, 2012 , 2013 ; Tate et al, 2017 , 2020 ). Evolved changes across the oxygen transport pathway contribute to this increased V O 2 max, and high capacities for cardiac output and tissue O 2 extraction at V O 2 max appear to play particularly important roles ( Lui et al, 2015 ; Mahalingam et al, 2017 ; Natarajan et al, 2015 ; Scott et al, 2015 ; Snyder et al, 1982 ; Storz et al, 2007 , 2010 , 2019 ; Tate et al, 2017 , 2020 ; Wearing et al, 2021 ; West et al, 2021 ). These differences in cardiac output and tissue O 2 extraction could result from changes in adrenergic regulation of the heart and vasculature and/or contractile function of the heart, but these possibilities have yet to be examined.…”

Angiotensin‑converting enzyme 2 alleviates pulmonary artery hypertension through inhibition of focal adhesion kinase expression

“…Only symptom-alleviation treatments, including endothelin receptor antagonists and phosphodiesterase inhibitors, in addition to strategies to promote arterial vasodilation, such as prostanoids and calcium channel blockers, can be used for clinical treatment ( 11 ). However, these treatments aforementioned can only partially effective in improving the symptoms and prolong life expectancy ( 12 ). Therefore, the present study aimed to develop more effective PAH treatment strategies and explore the mechanism underlying the pathological accumulation of PASMCs.…”