The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

People with high‐altitude ancestry exhibit distinct cellular, respiratory, and cardiovascular adaptive phenotypes relative to individuals with lowland ancestry. For example, Tibetans at high altitude exhibit higher ventilatory responses to hypoxia relative to Han Chinese at comparable altitude. We hypothesize Tibetans living at intermediate altitude maintain responses similar to those at high altitude. We measured levels of total hemoglobin ([Hb]), carboxyhemoglobin saturation (SpCO), and methemoglobin (MetHb), as well as the hypoxic and heart rate responses to acute hypoxia (HVR and HHR, respectively) under isocapnic and poikilocapnic conditions, in 21 individuals of Tibetan (n = 21) and Han Chinese (n = 16) ancestry residing at ~1300 m (~4327 ft) in Salt Lake City, Utah. To study ventilatory and heart rate responses to changes of CO2 during hypoxia (ΔVI /ΔEtCO2 and ΔHR/ΔEtCO2 respectively), we measured the difference in ventilation and heart rate between isocapnic (constant End‐tidal CO2) and poikilocapnic (with decreased End‐tidal CO2 due to hyperventilation) hypoxic conditions. Tibetans had lower [Hb] (p < 0.002), higher SpCO (p < 0.004), and higher MetHb (p < 0.02) levels compared to Han Chinese. [Hb] is negatively correlated with HHR in the Han Chinese (p < 0.05), but this was not observed in Tibetans. We did not find significant differences in HVR between Tibetans and Han Chinese, in contrast to previous reports at high altitude; however, we found that Tibetans exhibited a blunted HHR during poikilocapnic hypoxia (p < 0.03) relative to Han Chinese. We did not find differences in the ΔVI /ΔEtCO2 between the two groups, but Tibetans had lower ΔHR/ΔEtCO2 with more negative values compared to Han Chinese (p < 0.01). We also found that the correlation between HVR and HHR is similar for both groups during isocapnia, but the slopes of these correlations are significantly different in poikilocapnia (p < 0.003) with a positive relationship observed only in Tibetans (p < 0.006). Our results show that, at intermediate altitude, individuals with Tibetan ancestry have lower levels of [Hb], higher levels of Hb metabolites, and exhibit an attenuated heart rate response to hypoxia. The correlation between ventilatory and heart rate responses to hypoxia is similar between groups during isocapnia but is decreased during poikilocapnic hypoxia (with lower levels of CO2 due to hyperventilation) in Han Chinese but not Tibetans, suggesting a CO2‐dependent effect on HR in Han Chinese but not in Tibetans. Therefore, Hb levels and metabolism but not the HVR to hypoxia may be maintained in individuals with Tibetan ancestry at intermediate altitudes. Correlations in poikilocapnic vs. isocapnic hypoxia may suggest an attenuated effect of CO2 on heart rate during hypoxia in people with Tibetan ancestry.

Population living at high altitudes for hundreds of generations exhibit distinct respiratory and cardiovascular responses to hypoxia relative to other populations. The extent of these differences at intermediate altitude is less understood and could provide important insight into ancestry specific physiological responses in the absence of hypoxia. We hypothesized that Tibetans living at intermediate altitude (1300 m, 4327 ft) exhibit an increased hypoxic ventilatory response (HVR) and an elevated hypoxic heart rate response (HHR) compared to Han Chinese examined at the same altitude. To estimate O2 sensitivity, we measured ventilation (VI), heart rate (HR) and O2 saturation (Sat) under hyperoxic conditions (30% O2) and then during a hypoxic stimulus (10% minimum desaturation) keeping end‐tidal CO2 (EtCO2) levels constant (isocapnia) or allowing changes in the EtCO2 (poikilocapnia). We quantified HVR and HHR as change in VI and HR between hyperoxia and hypoxia standardized per the change in O2 Sat (ΔVI/ΔSat and ΔHR/ΔSat respectively). To estimate CO2 sensitivity, we measured changes in VI and HR responses between poikilocapnic and isocapnic hypoxia and standardized these changes per change in EtCO2 (ΔVI/ΔEtCO2 and ΔHR/ΔEtCO2 respectively). We did not find significant differences in ΔVI/ΔSat and ΔVI/ΔEtCO2 between Tibetan and Han Chinese during isocapnic and poikilocapnic hypoxia. The ΔHR/ΔSat between populations during isocapnic hypoxia was also not significantly different. However, Tibetans exhibited a blunted ΔHR/ΔSat during poikilocapnic hypoxia compared to Han Chinese (35.8% decrease, p < 0.02) with a significant ancestry effect in women (37.6% decrease, p < 0.009). The mean value of ΔHR/ΔEtCO2 was positive in the Han Chinese group but negative in Tibetan (169% difference, p < 0.02), indicating that Tibetans had a blunted HR response when CO2 is not controlled. Our results show that HVR responses in Tibetan individuals with high‐altitude ancestry is not different than Han Chinese residents at comparable intermediate altitude, but the HHR to hypoxia during poikilocapnia is blunted in individuals with Tibetan ancestry. These results suggest that, at intermediate altitude, individuals with Tibetan ancestry exhibit an attenuated heart rate response to hypoxia due to an increased contribution of the CO2 chemosensory response. Support or Funding Information Supported by NIH 1RO1HL145470 and R01 HL‐081823.

Populations living at high altitude have been subjected to the selective pressure of hypoxia due to low atmospheric pressure for hundreds of generations. Adaptive genetic signals are apparent in the genomes of present-day populations, but the links to physiological changes and underlying mechanisms are not completely understood. Our recent physiological studies revealed that Tibetans residing at intermediate altitude (2200 m; 13,780 ft) have lower hemoglobin concentration ([Hb]) and elevated carbon monoxide (CO) relative to other populations resident at the same altitude. Our previous genetic studies revealed that Tibetans residing at 4200 m (13,780 ft) exhibit a haplotype (20 kilobases) encompassing the Heme Oxygenase 2 (HMOX2) gene region. Heme oxygenase 2 protein produces carbon monoxide (CO) as a byproduct of hemoglobin breakdown. We hypothesize that HMOX2 underlies the observed CO levels at high altitude. We further hypothesize that regulatory variants could be linked to elevated heme oxygenase activity and, therefore, elevated CO levels in people of Tibetan ancestry.We measured carboxyhemoglobin (COHb) in Tibetan (n = 10) and Han Chinese (n = 8) male residents of Xining (2,200 m; 7,218 ft), China, using a co-oximeter and Tibetan (13 women, 8 men) and Han Chinese (6 women, 10 men) residents of Salt Lake City, Utah (1,413 m/4,637 ft) with a finger pulse oximeter. In the Xining cohort, COHb levels were 97% higher in Tibetans (1.01 ± 0.59 %) compared to their Han Chinese counterparts (0.51 ± 0.39 %, p < 0.048). This result was replicated in Salt Lake City, where Tibetans exhibited significantly higher COHb (4.31 ± 0.48%) compared to Han Chinese (2.00 ± 0.6%, p = 0.004).We also examined localized signals of natural selection (Composite of Multiple Signals test, CMS) from 27 previously published Tibetan genomes and identified single nucleotide variants (SNVs) within the selected haplotype with potential functional impacts on heme-oxygenase expression. Eleven variants were located within the promoter region of the HMOX2 gene. These variants exhibit significant delta allele frequencies (DAF) between Tibetans and Han Chinese (DAF > 0.2, p < 0.005) and are in high linkage disequilibrium (R2 > 0.9) in both populations. Literature and in-silico prediction tools (CIS-BP, JASPAR) indicate some of these variants have a potential gain-of-function roles as transcription factor binding sites.These results suggest adaptive, regulatory variants in HMOX2 may contribute to the observed increased endogenous CO in highland Tibetans, conferring protection from the selective stresses of high-altitude hypoxia. This project is funded by NIH R01HL145470. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypobaric hypoxia exerts a significant evolutionary pressure on highlanders who have resided at high altitude for thousands of years. This evolutionary pressure has resulted in signatures of natural selection within native highlanders’ genomes, some of which associate with adaptive physiological traits. Our recent analyses examined the overlap of a priori functional candidate genes and genes identified in the composite of multiple signals test of selection in 40 Andean genomes. We identified ICAM1, which encodes the intercellular adhesion molecule 1 protein, as one of the top 10 candidate genes of positive selection in this highland population. We utilized LDproxy and CADD score analysis to prioritize variants of functional relevance in this gene. The single-nucleotide variant (SNV) rs1799969, located in exon 4, exhibited the highest CADD score of 22.0. We genotyped rs1799969 in a larger cohort of 255 Andean highlanders and found that 68% of Andeans have at least one copy of the SNV, compared to 6% and 20% in worldwide and American populations, respectively, from the 1000 Genomes data set. Given the soluble form of ICAM1 is elevated in patients with COPD, atherosclerosis, coronary heart disease, and other cardiometabolic phenotypes, and rs1799969 is associated with less soluble ICAM1 in larger, worldwide cohorts, we tested the hypothesis that putatively adaptive copies of ICAM1 would be associated with blood pressure in the high-altitude Andean cohort. We found that more copies of the putatively adaptive haplotype containing rs1799969 is associated with lower systolic blood pressure (p-value = 0.012 for 0 vs 2 alleles, 0.028 for 0 vs 1 allele; effect size = 7.1mmHg for males, 13.5mmHg for females; NS diastolic blood pressure), whereby the effect size of the number of adaptive gene copies on systolic blood pressure is comparable to commonly prescribed medications and orders of magnitude larger than previous genetic association studies of blood pressure (~1.5mmHg for rare variants, ~0.5mmHg for common variants). Because ICAM1 is activated by hypoxia, it is plausible that rs1799969 may play a protective physiological role in the context of chronic hypoxia in Andean highlanders. Hypertension is one of the strongest modifiable risk factors for cardiometabolic disease, and this may be especially relevant in hypobaric hypoxia, where chronic activation of sympathetic activity can increase blood pressure. Additionally, elevated blood pressure is a known causative agent for diseases that are exacerbated at high altitude, such as pre-eclampsia. However, studies of hypertension in native highland populations have mixed results, often reporting conflicting associations depending on the population being studied, warranting further investigations into hypertension prevalence in various highland populations and genetic factors that may impact blood pressure. Supported by NIH 1R01HL145470 to TSS This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Populations living at high altitudes exhibit distinct cardiovascular and ventilatory responses to hypoxia, which may result from exposure to the selective pressure of chronic hypoxia throughout hundreds of generations at high altitude. Compared to Andean highlanders and some acclimatized lowlanders, many Tibetans show an increased hypoxic ventilatory response (HVR) and lower hemoglobin concentration ([Hb]). While the effects of menopause on [Hb] have been well studied, its effects on HVR and heart rate responses to hypoxia (HHRR) in Tibetan women residing at high altitude have not been elucidated. We hypothesized that hypoxic ventilatory and heart rate responses to hypoxia decrease with menopausal status in Tibetan women, suggesting a change of adaptation during post-reproductive years in women. We measured minute ventilation (VI) and heart rate (HR) during room air and acute hypoxia in 376 Tibetan women (age range 46-86 years old) living in in Mustang, Nepal (>11,482ft / 3,500m) and compared responses between pre- and post-menopausal groups (mean ± SEM). Using a rebreathing system, we induced hypoxia to produce events of at least 10% desaturation (from 91 ± 0.2% to 78 ± 0.2%), expressed HVR and HRR as -ΔVI / ΔSpO2 and -ΔHR / ΔSpO2, respectively, and tested for associations between HVR and HHRR with age and [Hb]. HVR, HHRR, and [Hb] associated negatively with age in the post- but not pre-menopausal group. During hypoxia, post-menopausal women had lower VI (14.2 ± 0.2 L/min) and HR (80 ± 1 BPM) when compared (p<0.01) to pre-menopausal women (16.9 ± 0.4 L/min for VI and 85 ± 1 BPM for HR). VI was also lower in room air conditions (p<0.01) for post-menopausal (11.5 ± 0.1 L/min) versus pre-menopausal women (12.6 ± 0.2 L/min). HVR and HHRR was lower in post- (0.21 ± 0.01 L/%O2 and 0.65 ± 0.02 BPM/%O2 respectively) versus pre-menopausal women (HVR: 0.34 ± 0.03 L/%O2 and HHRR: 0.92 ± 0.05 BPM/%O2). Pre-menopausal women also exhibited negative correlations with HVR and HHRR with increasing [Hb]; however, these correlations were not significant in the post-menopausal group. A non-blunted HVR is a hallmark of adaptation in Tibetans, and physiological changes observed in Tibetan women during later life stages may result in a loss of such traits. These data suggest a hypothesis of menopause-related loss, or change, of adaptation to high-altitude hypoxia among middle-aged to elderly Tibetan women. Supported by NSF award 1831530 to CMB and NIH 1R01HL145470 to TSS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.