Tissot van Patot, Martha C. and Max Gassman. Hypoxia: Adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α. High Alt. Med. Biol. 12:157–167, 2011.—Living at high altitude is demanding and thus drives adaptational mechanisms. The Tibetan population has had a longer evolutionary period to adapt to high altitude than other mountain populations such as Andeans. As a result, some Tibetans living at high altitudes do not show markedly elevated red blood cell production as compared to South American high altitude natives such as Quechuas or Aymaras, thereby avoiding high blood viscosity creating cardiovascular risk. Unexpectedly, the responsible mutation(s) reducing red blood cell production do not involve either the gene encoding the blood hormone erythropoietin (Epo), or the corresponding regulatory sequences flanking the Epo gene. Similarly, functional mutations in the hypoxia-inducible transcription factor 1α (HIF-1α) gene that represents the oxygen-dependent subunit of the HIF-1 heterodimer, the latter being the main regulator of over 100 hypoxia-inducible genes, have not been described so far. It was not until very recently that three independent groups showed that the gene encoding HIF-2α, EPAS-1 (Wenger et al. 1997), represents a key gene mutated in Tibetan populations adapted to living at high altitudes (Beall et al. 2010, Yi et al. 2010, Simonson et al. 2010). Hypoxia-inducible transcription factors were first identified by the description of HIF-1 (Semenza et al. 1991, 1992), which was subsequently found to enhance transcription of multiple genes that encode proteins necessary for rescuing from hypoxic exposure, including erythropoietic, angiogenic and glycolytic proteins. Then HIF-2 was identified (Ema et al. 1997; Flamme et al. 1997; Hogenesch et al. 1997; and Tian et al. 1997) and although it is highly similar to HIF-1 and has the potential to bind (Camenisch et al. 2001) and mediate (Mole et al. 2009) many of the same genes as HIF-1, its biological actions in response to hypoxia are distinct from those of HIF-1 (reviewed by Loboda et al. 2010). By now, several of these HIF-2 mediated processes have been implicated in the human response to high altitude exposure including erythropoiesis (Kapitsinou et al. 2010), iron homeostasis (Peyssonnaux et al. 2008), metabolism (Shohet et al. 2007; Tormos et al. 2010; Biswas et al. 2010; Rankin et al. 2009) and vascular permeability (Chen et al. 2009; Tanaka et al. 2005), among others. Clearly, mutation of EPAS-1 has the potential to bring far more advantage when adapting to high altitude than solely mutating the Epo gene.

Adequate acclimatization time to enable adjustment to hypoxic conditions is one of the most important aspects for mountaineers ascending to high altitude. Accordingly, most reviews emphasize mechanisms that cope with reduced oxygen supply. However, during sojourns to high altitude adjustment to elevated iron demand is equally critical. Thus in this review we focus on the interaction between oxygen and iron homeostasis. We review the role of iron 1) in the oxygen sensing process and erythropoietin (Epo) synthesis, 2) in gene expression control mediated by the hypoxia-inducible factor-2 (HIF-2), and 3) as an oxygen carrier in hemoglobin, myoglobin, and cytochromes. The blood hormone Epo that is abundantly expressed by the kidney under hypoxic conditions stimulates erythropoiesis in the bone marrow, a process requiring high iron levels. To ensure that sufficient iron is provided, Epo-controlled erythroferrone that is expressed in erythroid precursor cells acts in the liver to reduce expression of the iron hormone hepcidin. Consequently, suppression of hepcidin allows for elevated iron release from storage organs and enhanced absorption of dietary iron by enterocytes. As recently observed in sojourners at high altitude, however, iron uptake may be hampered by reduced appetite and gastrointestinal bleeding. Reduced iron availability, as observed in a hypoxic mountaineer, enhances hypoxia-induced pulmonary hypertension and may contribute to other hypoxia-related diseases. Overall, adequate systemic iron availability is an important prerequisite to adjust to high-altitude hypoxia and may have additional implications for disease-related hypoxic conditions.

Erythropoietin (Epo) treatment increases hematocrit (Htc) and, consequently, arterial O ₂ content. This in turn improves exercise performance. However, because elevated blood viscosity associated with increasing Htc levels may limit cardiac performance, it was suggested that the highest attainable Htc may not necessarily be associated with the highest attainable exercise capacity. To test the proposed hypothesis that an optimal Htc in acute and chronic Epo-treated mice exists—i.e., the Htc that facilitates the greatest O ₂ flux during maximal exercise—Htc levels of wild-type mice were acutely elevated by administering novel erythropoiesis-stimulating protein (NESP; wtNESP). Furthermore, in the transgenic mouse line tg6 that reaches Htc levels of up to 0.9 because of constitutive overexpression of human Epo, the Htc was gradually reduced by application of the hemolysis-inducing compound phenylhydrazine (PHZ; tg6PHZ). Maximal cardiovascular performance was measured by using telemetry in all exercising mice. Highest maximal O ₂ uptake and maximal time to exhaustion at submaximal exercise intensities were reached at Htc values of 0.58 and 0.57 for wtNESP, and 0.68 and 0.66 for tg6PHZ, respectively. Rate pressure product, and thus also maximal working capacity of the heart, increased with elevated Htc values. Blood viscosity correlated with Apart from the confirmation of the Htc hypothesis, we conclude that tg6PHZ adapted better to varying Htc values than wtNESP because of the higher optimal Htc of tg6PHZ compared to wtNESP. Of note, blood viscosity plays a critical role in limiting exercise capacity.

A strong mechanistic link between the regulation of iron homeostasis and oxygen sensing is evident in the lung, where both systems must be properly controlled to maintain lung function. Imbalances in pulmonary iron homeostasis are frequently associated with respiratory diseases, such as chronic obstructive pulmonary disease and with lung cancer. However, the underlying mechanisms causing alterations in iron levels and the involvement of iron in the development of lung disorders are incompletely understood. Here, we review current knowledge about the regulation of pulmonary iron homeostasis, its functional importance, and the link between dysregulated iron levels and lung diseases. Gaining greater knowledge on how iron contributes to the pathogenesis of these diseases holds promise for future iron-related therapeutic strategies.

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother–child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.

Undisturbed functioning of the blood–brain barrier (BBB) crucially depends on paracellular signaling between its associated cells; particularly endothelial cells, pericytes and astrocytes. Hypoxic and ischemic injuries are closely associated with disturbed BBB function and the contribution of perivascular cells to hypoxic/ischemic barrier regulation has gained increased attention. Regardless, detailed information on the basal hypoxic/ischemic responses of the barrier-associated cells is rare and the outcome of such cell-specific responses on BBB modulation is not well understood. This study investigated crucial parameters of hypoxic/ischemic adaptation in order to characterize individual perivascular cell responses to stress conditions.