Control of breathing and the circulation in high-altitude mammals and birds.

CBA-09775; No of Pages 9 Comparative Biochemistry and Physiology, Part A xxx (2014) xxx–xxx

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Comparative Biochemistry and Physiology, Part A journal homepage: www.elsevier.com/locate/cbpa

Review

Control of breathing and the circulation in high-altitude mammals and birds Catherine M. Ivy ⁎, Graham R. Scott Department of Biology, McMaster University, Hamilton, ON, Canada

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Article history: Received 30 June 2014 Received in revised form 17 October 2014 Accepted 18 October 2014 Available online xxxx Keywords: Adrenergic receptors Carotid body Chemoreceptors Gas exchange High elevation Ontogeny Pulmonary vasculature Systemic blood flow Hypoxic ventilatory response Ventilatory acclimatization to hypoxia

a b s t r a c t Hypoxia is an unremitting stressor at high altitudes that places a premium on oxygen transport by the respiratory and cardiovascular systems. Phenotypic plasticity and genotypic adaptation at various steps in the O2 cascade could help offset the effects of hypoxia on cellular O2 supply in high-altitude natives. In this review, we will discuss the unique mechanisms by which ventilation, cardiac output, and blood flow are controlled in high-altitude mammals and birds. Acclimatization to high altitudes leads to some changes in respiratory and cardiovascular control that increase O2 transport in hypoxia (e.g., ventilatory acclimatization to hypoxia). However, acclimatization or development in hypoxia can also modify cardiorespiratory control in ways that are maladaptive for O2 transport. Hypoxia responses that arose as short-term solutions to O2 deprivation (e.g., peripheral vasoconstriction) or regional variation in O2 levels in the lungs (i.e., hypoxic pulmonary vasoconstriction) are detrimental at in chronic high-altitude hypoxia. Evolved changes in cardiorespiratory control have arisen in many high-altitude taxa, including increases in effective ventilation, attenuation of hypoxic pulmonary vasoconstriction, and changes in catecholamine sensitivity of the heart and systemic vasculature. Parallel evolution of some of these changes in independent highland lineages supports their adaptive significance. Much less is known about the genomic bases and potential interactive effects of adaptation, acclimatization, developmental plasticity, and trans-generational epigenetic transfer on cardiorespiratory control. Future work to understand these various influences on breathing and circulation in high-altitude natives will help elucidate how complex physiological systems can be pushed to their limits to maintain cellular function in hypoxia. © 2014 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . Phenotypic plasticity and high-altitude hypoxia. . . . . . . . . . 2.1. Responses of adult lowlanders to high-altitude hypoxia. . . 2.1.1. The hypoxic ventilatory response. . . . . . . . . 2.1.2. Hypoxic pulmonary vasoconstriction. . . . . . . 2.1.3. The autonomic nervous system in hypoxia . . . . 2.2. Developmental plasticity. . . . . . . . . . . . . . . . . 2.3. Trans-generational transfer . . . . . . . . . . . . . . . . 3. Genotypic adaptation and high-altitude hypoxia. . . . . . . . . . 3.1. Unique traits of highland taxa . . . . . . . . . . . . . . 3.2. Interactions between adaptation and phenotypic plasticity . 4. Conclusions and perspectives . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Department of Biology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada, L8S 4K1. Tel.: +1 905 525 9140. E-mail address: [email protected] (C.M. Ivy).

http://dx.doi.org/10.1016/j.cbpa.2014.10.009 1095-6433/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: Ivy, C.M., Scott, G.R., Control of breathing and the circulation in high-altitude mammals and birds, Comp. Biochem. Physiol., A (2014), http://dx.doi.org/10.1016/j.cbpa.2014.10.009

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C.M. Ivy, G.R. Scott / Comparative Biochemistry and Physiology, Part A xxx (2014) xxx–xxx

1. Introduction High-altitude environments pose multiple challenges to the organisms that inhabit them, including cold temperatures, low humidity, and hypobaric hypoxia. Unlike temperature and humidity, which can fluctuate daily and seasonally, the low partial pressure of oxygen (PO2) at high altitude is unavoidable and unremitting. For example, many high-altitude human and mammal populations live, grow, and reproduce at over 4,000 m elevation where the PO2 is roughly 60% of that at sea level. Some birds are known to fly at higher altitudes as a part of their natural migration, despite the fact that flight is an oxygen demanding process that becomes all the more challenging in a hypoxic environment (Ward et al., 2002; Hawkes et al., 2013). This implies that of the two general strategies for coping with hypoxia – reduction of oxygen demands by metabolic depression (Boutilier, 2001) and/or increases in the supply of oxygen through transport pathways (Hochachka, 1986) – only the latter is a feasible option for the survival and fitness of animals native to high altitude. Performance in high-altitude hypoxia is enhanced by increases in the capacity to transport oxygen along the oxygen cascade, comprised of ventilation, pulmonary oxygen diffusion, circulation of oxygen in the blood, and tissue oxygen diffusion and utilization (Fig. 1). This could foreseeably be achieved through phenotypic plasticity – responses to high-altitude exposure that occur within the lifetime of an individual – or evolved heritable (e.g., genetic) changes that modify the capacity for oxygen transport at steps in the cascade. Although the term ‘adaptation’ can often be used in both contexts, we will restrict its use to traits that evolved by natural selection. The highland phenotype – arising through adaptation or various mechanisms of phenotypic plasticity – can include changes in many morphological traits that enhance the capacity for oxygen diffusion, including increases in the surface area of the pulmonary air-blood interface (Hsia et al., 2005, 2007; Ravikumar et al., 2009; Scott et al., 2011), increases in the capillarity of peripheral tissues (León-Velarde et al., 1993; Mathieu-Costello et al., 1998; Scott et al., 2009), and a redistribution of mitochondria towards capillaries to a subsarcolemmal location in the skeletal muscle (Scott et al., 2009). The highland phenotype can also differ from that of lowlanders in how the blood binds O2, mediated by evolved and acclimatization-induced changes in haemoglobin concentration

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and/or haemoglobin-O2 affinity (Monge and León-Velarde, 1991; Nikinmaa, 2001; Weber and Fago, 2004; Storz and Moriyama, 2008). These components of the highland phenotype are extremely important at high altitudes, and have been well reviewed elsewhere (Monge and León-Velarde, 1991; Storz et al., 2010; Scott, 2011). In the spirit of celebrating the impressive career of Bill Milsom, our attention on the unique physiology of high-altitude animals will focus on the mechanisms that control breathing and the circulation in hypoxia – a topic that is near and dear to Bill’s heart and to which he has devoted a great deal of attention. We write this article with deep-felt thanks to Bill for many years of inspiring research and for being a true ambassador of comparative physiology. 2. Phenotypic plasticity and high-altitude hypoxia The response to high-altitude hypoxia in lowland animals provides insight into whether phenotypic plasticity can generally be regarded to facilitate or impede evolutionary adaptation in animals that colonize high altitudes (Storz et al., 2010). Many rapid physiological responses to hypoxia in adult animals occur within minutes to hours of acute exposure, which can be subsequently modulated by adjustments in control systems after longer durations of chronic acclimatization to hypoxia. Hypoxia exposure during prenatal and postnatal development can have life-long persistent effects that differ substantially from the hypoxia responses observed in adults (Bavis, 2005). Parental exposure to hypoxia may even have long-lasting consequences that are transmitted to offspring by epigenetic mechanisms, akin to trans-generational plasticity, but we are only just beginning to understand how parental effects can influence respiratory and cardiovascular physiology (Ho and Burggren, 2010). 2.1. Responses of adult lowlanders to high-altitude hypoxia 2.1.1. The hypoxic ventilatory response The hypoxic ventilatory response (HVR) is initiated within one breath of a reduction in arterial PO2, and involves an increase in breathing that helps maintain O2 transport (Powell et al., 1998; Brutsaert, 2007). The carotid body immediately senses the drop in arterial PO2 and stimulates afferent sensory discharge in the carotid sinus nerve

Lowlander Highlander

Lung

A

B

Artery

Capillary

C

D

E

F

O2 Cell ADP

ATP O2 Tension

Fig. 1. The oxygen cascade – oxygen tension (PO2) at each step in the pathway could be increased in high-altitude natives by genotypic adaptation and/or phenotypic plasticity. PO2 declines along the length of capillaries as O2 diffuses into target tissues, so a range of capillary PO2 drives diffusion into tissues. PO2 also declines with distance from capillaries, so there should be a range of cellular PO2 depending on both capillary PO2 and diffusion distance. Adapted from (Taylor and Weibel, 1981) and (Scott, 2011).



(Gonzalez et al., 1994; Nurse, 2010; Teppema and Dahan, 2010). Glomus (type I) cells in the carotid body are the primary sensor and release the main excitatory neurotransmitters (e.g., ATP, acetylcholine), but discharge from the carotid body can also be regulated by autocrine and paracrine mechanisms by the release of neuromodulators (e.g., dopamine, adenosine) from type I or type II cells (Nurse, 2010; Piskuric and Nurse, 2013). The nature of the O2 sensor in glomus cells is controversial, and could include membrane bound channels (e.g., O2-sensitive K+ channels or Na+ channels), O2 sensitive enzymes (e.g., NADPH oxidase), heme proteins, kinases (e.g., AMP kinase), or mitochondria (Kumar and Prabhakar, 2012). Nerve impulses transmitted from the carotid sinus nerve reach the nucleus tractus solitaries (NTS) in the medulla, which then integrates the carotid body signal and delivers information about chemoreceptive drive to the respiratory central pattern generator (Gonzalez et al., 1993; Haxhiu et al., 1995; Milsom, 2010; Nurse, 2010). The resulting increase in efferent motor output in neurons innervating the respiratory muscles stimulates breathing frequency and/or tidal volume. The resulting increase in total ventilation increases alveolar PO2 (parabronchial PO2 in the case of birds) at the gas exchange surface, and thus helps minimize the drop in arterial PO2 and oxygen content. Increases in ventilation are maintained for prolonged periods at elevation in mammals (Duffin and Mahamed, 2003; Brutsaert, 2007), but the acute HVR is modulated by numerous neural and physiological factors at different time domains of the response (Barnard et al., 1987; Powell et al., 1998). In particular, prolonged durations at high altitude often lead to further increases in ventilation and enhanced ventilatory sensitivity to hypoxia (Powell et al., 1998, 2000a,b; Yilmaz et al., 2005; Slessarev et al., 2010a,b) that should help increase alveolar and arterial PO2 (Fig. 1). This ventilatory acclimatization to hypoxia (VAH) occurs due to increases in both the chemoreceptor sensitivity of the carotid bodies and the responsiveness of central integration sites to afferent inputs from the carotid bodies (Vizek et al., 1987; Dwinell and Powell, 1999; Wilkinson et al., 2010; Kumar and Prabhakar, 2012). The former likely results at least in part from changes in ion channel densities and neurotransmitter stores in the glomus cells, glomus cell hypertrophy and/or hyperplasia (Wang et al., 2008), cell differentiation (Pardal et al., 2007), and/or neovascularization (Kusakabe et al., 1993; Hempleman, 1995, 1996; Prabhakar and Jacono, 2005). Increases in CNS responsiveness to afferent chemoreceptor information as a mechanism of VAH is not as well understood, but probably involves changes in glutamatergic signalling in the NTS (Reid and Powell, 2005; Pamenter et al., 2014). Many of these changes with VAH could be initiated by the stabilization of hypoxia inducible factors and the resulting expression of hypoxia-responsive genes in each location (Powell and Fu, 2008; Kumar and Prabhakar, 2012; Slingo et al., 2014). In birds, VAH is not well understood and the effects of acclimatization have been inconsistent (Black and Tenney, 1980a; Powell et al., 2000b). Changes in arterial carbon dioxide tension (PCO2) and pH also affect breathing during high-altitude hypoxia (Slessarev et al., 2010a,b). The HVR increases CO2 loss and causes a secondary respiratory hypocapnia that can lead to blood alkalosis. Increases in CO2/H+ strongly stimulate breathing via the carotid bodies and the central CO2 chemoreceptors. Hypocapnia and alkalosis will therefore act at cross-purposes to the HVR, by inhibiting ventilation and impeding oxygen transport (Scott and Milsom, 2009). However, changes in CO2/H+ in arterial blood and CSF are not sufficient on their own to explain the time-dependent increase in ventilation during acclimatization, because chronic highaltitude hypoxia is associated with further decreases in PCO2 and the secondary increases in ventilation with VAH are not associated with recovery of pH in arterial blood or cerebrospinal fluid (Bureau and Bouverot, 1975; Powell, 2007). Nevertheless, it is possible that changes in the CO2/pH sensitivity of breathing could influence the progressive increases in breathing at high altitudes (Dwinell et al., 1997; Fatemian and Robbins, 1998).

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2.1.2. Hypoxic pulmonary vasoconstriction The pulmonary vascular responses to high-altitude hypoxia in lowland mammals generally impair O2 transport. The pulmonary vasculature constricts when exposed to hypoxia, a response that can be important for gas exchange at sea level because it helps match blood flow to regional variation in ventilation and alveolar PO2 in the lungs. By contrast, this induces a global pulmonary vasoconstriction at high altitudes, because hypoxia exists throughout the entirety of the lungs (Heath et al., 1973; Banchero, 1987; Vizek et al., 1987; Nakanishi et al., 1996; Ge et al., 1998; Powell et al., 2004; Naeije and Dedobbeleer, 2013). This can impair pulmonary O2 diffusion by diverting blood flow away from the gas exchange surface to pulmonary shunt vessels (Lovering et al., 2008), and can result in pulmonary hypertension that causes fluid to leak into the air spaces and thicken the O2 diffusion barrier (Eldridge et al., 2006; Maggiorini et al., 2001; Fig. 1 B). Smooth muscle cells in the pulmonary arteries mediate pulmonary vasoconstriction when decreases in alveolar PO2 are sensed directly, causing inhibition of O2 sensitive K+ channels (Kv), membrane depolarization, and Ca2+ influx (Somlyo and Somlyo, 1994; Archer et al., 2001; Hong et al., 2004; Moudgil et al., 2005). Hypoxia may be sensed in these cells by sensors that detect the cellular consequences of hypoxia exposure, including increases in AMP/ATP sensed by AMP-activated protein kinase (AMPK) (Evans and Ward, 2009), altered levels of ROS production by the mitochondria (Evans and Ward, 2009), or increases in the production of hydrogen sulphide (H2S) (Olson et al., 2006). Over the course of prolonged high-altitude acclimatization, pulmonary vasoconstriction and hypertension can lead to a muscularization of the pulmonary arteries and right ventricle hypertrophy (Heath et al., 1973; Nakanishi et al., 1996; Sizlan et al., 2008). However, acclimation can also reduce Kv channel expression in pulmonary arterial smooth muscle cells, which blunts oxygen sensitivity and can help partially (but not completely) offset pulmonary vasoconstriction and hypertension (Wang et al., 1997; Hong et al., 2004). In contrast to mammals, birds do not experience hypoxic pulmonary vasoconstriction (Powell et al., 1985; West, 2009; Scott, 2011; Scott et al., 2011). Pulmonary arterial pressure only rises in response to increases in pulmonary blood flow, and not due to changes in vascular resistance (Black and Tenney, 1980b; Faraci et al., 1984; West et al., 2007). The rigid structure of the parabronchial avian lung also makes it better able to withstand stress failure in response to increases in pulmonary pressure than the mammalian lung, and birds may therefore be less susceptible to hypoxic pulmonary oedema (West et al., 2007; West, 2009). 2.1.3. The autonomic nervous system in hypoxia Acute hypoxia activates the sympathetic nervous system, which acts to increase heart rate, systemic vascular resistance, and blood pressure (Hainsworth and Drinkhill, 2007). This is partly mediated by direct hypoxic stimulation of the carotid bodies, which increases afferent neural activity to the cardiovascular control centre of the medulla. The sympathetic nervous system is also activated as a secondary consequence of the indirect effects of hypoxia, including (i) the response of pulmonary stretch receptors to the increases in breathing during hypoxia (Marshall, 1994; Reis et al., 1994) and (ii) baroreceptor responses to hypotension resulting from the direct vasodilatory actions of hypoxia and other local factors on vascular smooth muscle in the systemic circulation (Hainsworth et al., 2007). Sympathetic activation is a key protective defense against acute hypoxia, because the strong vasoconstriction in most peripheral tissues helps redistribute blood flow to essential core tissues such as the heart and brain. Sympathetic activity remains high after prolonged periods at high altitude (Mazzeo et al., 1994; Calbet, 2003; Dhar et al., 2014), but heart rate tends to return to sea level values after acclimatization (Vogel and Harris, 1967; Foster et al., 2014). Although this may result in part from a reduction in chemosensory drive arising from the increase in arterial O2 content with acclimatization (Gonzalez et al., 1993), it is also strongly contributed to by a desensitization of β-


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adrenergic receptors and a reduction in β-adrenoreceptor density in the cardiac tissue (Voelkel et al., 1981; Light et al., 1984; Reeves et al., 1987; Kacimi et al., 1992; León-Velarde et al., 2001a; Morel et al., 2003). Increases in α1-adrenergic and M2 muscarinic receptor densities, as well as increased parasympathetic activity, have also been observed with high-altitude acclimatization (Kacimi et al., 1993; León-Velarde et al., 1996, 2001a; Morel et al., 2003). The resulting hypoxia-induced decrease in cardiac chronotropic function is suggested to limit myocardial oxygen consumption, reduce maximum heart rate, and to protect the heart from hypoxia (Richalet et al., 1989, 1992). Activation of the sympathetic nervous system and the release of local vasoactive substances together regulate systemic vascular resistance and blood flow in hypoxia. Forearm vasodilation can occur in humans in response to acute hypoxia (Dinenno et al., 2003; Halliwill, 2003), which may occur through the actions of locally released nitric oxide (NO) and stimulation of β2-adrenoreceptors (Blauw et al., 1995; Weisbrod et al., 2001; Markwald et al., 2011). However, systemic vascular resistance and blood pressure usually increase with acute hypoxia, because the vasoconstrictor actions of α-adrenoreceptor activation tends to outweigh the factors that promote vasodilation (Hainsworth and Drinkhill, 2007). Prolonged acclimatization to high-altitude hypoxia shifts this balance towards vasodilation and partially alleviates the increased vascular resistance, by a mechanism that does not appear to involve changes in NO signalling (Coney et al., 2004). 2.2. Developmental plasticity The conditions experienced during development play an important role in shaping respiratory control systems. Hypoxia exposure during early life can lead to unique long-lasting effects on the control of breathing that are not always the same as those exhibited in hypoxia-exposed adults (Bavis, 2005; Bavis and Mitchell, 2008). Furthermore, the responses to hypoxia exposure during prenatal development can differ substantially from those exhibited in response to exposure during early postnatal life. Prenatal hypoxia causes a long-lasting increase in ventilation and the HVR in mammals, mirroring the changes that occur with VAH in hypoxia-acclimated adults (Gleed and Mortola, 1991; Peyronnet et al., 2000, 2007). The effects of prenatal hypoxia can persist for several weeks or more after normoxia is re-established. By comparison, VAH in adults is typically reversed at sea level after a comparable duration to that which induces VAH upon ascent (Powell et al., 1998). Maintenance of the effects of prenatal exposure has been associated with complex changes in post-natal dopamine expression, tyrosine hydroxylase (TH) activity, and norepinephrine turnover in the carotid bodies and/ or catecholaminergic regions of the medulla (Peyronnet et al., 2000, 2007). Conversely, prenatal hypoxia exposure has been shown to decrease normoxic ventilation and the HVR in newly hatched chicks (Szdzuy and Mortola, 2007), a response that differs from mammals but mirrors the effects of VAH in adult ducks (Powell et al., 2000a). Neonatal hypoxia exposure blunts or even abolishes the HVR, in contrast to VAH in adults and the effects of prenatal hypoxia (Brooks and Tenney, 1968; Okubo and Mortola, 1990; Lumbroso and Joseph, 2009). Proper development of the carotid bodies in neonatal mammals is believed to be tightly associated with arterial PO2 (Peyronnet et al., 2000; Bavis, 2005). The increase in arterial PO2 that occurs as breathing commences after birth at low altitude initially reduces carotid body activity, but activity soon adjusts to the new working PO2 range (Hertzberg et al., 1990; Carroll et al., 1993). It is possible that neonatal hypoxia affects the HVR in adults by disrupting this normal developmental transition by extending the hypoxaemia experienced in utero into postnatal life (Peyronnet et al., 2000; Bavis, 2005; Lumbroso et al., 2012). This delay could be responsible for blunting the HVR and reducing/silencing chemoreceptor responses in animals that are continually hypoxic from birth (Brooks and Tenney, 1968; Sterni et al., 1999; Yilmaz et al., 2005; McDonough et al., 2006; Lumbroso and Joseph,

2009). However, the blunting of the HVR by neonatal hypoxia could occur by mechanisms that do not involve peripheral chemoreceptors (Eden and Hanson, 1987; Bavis, 2005). There are sites in the central nervous system of neonates (possibly in the medulla, pons, and/or midbrain) that respond to hypoxia by inducing hypoxic ventilatory depression (Hill et al., 2013), and it is possible that neonatal hypoxia could prolong this inhibitory effect. However, some evidence suggests that neonatal hypoxia has no effect on phrenic nerve activity in response to hypoxia in later life, implying that neonatal hypoxia may blunt the HVR by reducing the response of chemoreflex components that are efferent to the phrenic nerve (such as neurotransmission at the neuromuscular junction, respiratory muscle activity, or breathing mechanics) rather than by reducing peripheral chemosensitivity (Bavis et al., 2004). In some cases, neonatal hypoxia has also been shown to raise resting ventilation in normoxia in later life, possibly by affecting central integration and ventilatory drive (Okubo and Mortola, 1990). Interestingly, the effects of neonatal hypoxia are much stronger in males than in females, possibly due to an important additional influence of the ovarian steroids progesterone and estradiol (Bayliss et al., 1987; León-Velarde et al., 2001b; Joseph et al., 2002; Bavis et al., 2004; Lumbroso et al., 2012). It is therefore likely that multiple neural and non-neural mechanisms contribute to the persistent blunting of the HVR that occurs in response to neonatal hypoxia. Developmental hypoxia can also have persistent effects on the pulmonary circulation that mimic the effects of hypoxia in adult mammals. Prenatal hypoxia causes pulmonary hypertension and vascular remodeling in fetuses and newborns of many mammalian species (Papamatheakis et al., 2013). The effects of prenatal hypoxia can persist after returning to normoxia, and may arise via changes in pulmonary vessel compliance, sensitivity to vasoactive substances, and the abundance of several regulators of vascular tone (e.g., nitric oxide synthase, heme oxygenase) (Jones et al., 2004; Herrera et al., 2010). Although the pulmonary vessels of birds are also sensitive to hypoxia during early development, this may serve to facilitate the right-to-left shunt through the ductus arteriosis (Ågren et al., 2007) since the response is not employed in response to hypoxia in later life (as discussed above). Furthermore, hypoxia exposure during in ovo development does not affect the acute hypoxia sensitivity of the intrapulmonary vessels in birds (Zoer et al., 2009). Developmental hypoxia also has effects on the systemic circulation that are similar to what occur with hypoxia exposure in later life. Heart rate, cardiac output, and femoral vascoconstrictor responses (acute hypoxia or catecholamines) are elevated in mammals that develop and are tested at high altitudes (Graf et al., 2006; Herrera et al., 2007). As for adults, this represents an important response to shortterm periods of oxygen deprivation in the fetus because it helps redistribute blood flow to essential tissues, but at least some effects of prenatal hypoxia (e.g., elevated blood pressure and heart rate variability) can persist in normoxia long after birth (Peyronnet et al., 2002). In ovo hypoxia in chickens also reduces blood flow, increases vascular resistance, and augments sympathetic innervation of the femoral artery (Ruijtenbeek et al., 2000; Iversen et al., 2014). Femoral vascoconstriction response to catecholamine stimulation is also increased after many weeks of ex ovo development in normoxia (Ruijtenbeek et al., 2003). These effects of developmental hypoxia can even persist into adulthood in humans, and increase vulnerability to cardiovascular disease (Zhang, 2005). 2.3. Trans-generational transfer Control of breathing and the circulation at high altitudes could foreseeably be influenced by parental effects, such as epigenetic mechanisms that can transfer heritable phenotypes across generations without any alteration of gene sequence. Transmission of signals from parents to their offspring during development can alter offspring behaviour, morphology, and gene expression (Groothuis et al., 2005; Ho and



Burggren, 2010; Kappeler and Meaney, 2010). In birds, reptiles, amphibians, and fish, maternal influences that change egg composition have been shown to affect offspring physiology (Bernardo, 1996; Finkler et al., 1998; Dzialowski et al., 2009). In mammals, stressors to the mother during pregnancy can alter offspring phenotypes (Vieau et al., 2007; Darnaudéry and Maccari, 2008; Briana and Malamitsi-Puchner, 2009; Mastorci et al., 2009). Key molecular mechanisms of transgenerational transfer can include RNA signalling (non-coding RNA, microRNA), DNA methylation, and histone modifications, all of which can lead to inherited changes in phenotype by regulating the expression of genes (Prabhakar, 2013). Few studies have examined the role of parental effects and epigenetics in response to hypoxia in the ventilatory and cardiovascular systems of mammals and birds, but trans-generational responses to hypoxia have been observed in zebrafish. F1 generation zebrafish bred from hypoxia-exposed parents exhibited increased hypoxia resistance and heart rate (Jacob et al., 2002; Ho and Burggren, 2012), suggesting that parental effects (or possibly a direct effect of hypoxia on germline cells) may alter the cardiorespiratory responses to hypoxia (Jablonka and Raz, 2009; Burton and Metcalfe, 2014). The nature of trans-generational transfer of cardiorespiratory phenotypes at high altitudes – including whether it is adaptive or maladaptive – and its potential for being targeted by selection during high-altitude adaptation awaits future research. 3. Genotypic adaptation and high-altitude hypoxia Overlaid upon the effects of phenotypic plasticity in species and populations that are indigenous to high altitude are evolved changes in physiology that may have been favoured by natural selection. Genotypic adaptations in respiratory and cardiovascular physiology appear to have occurred in numerous highland taxa (Monge and León-Velarde, 1991; Storz et al., 2010; Scott, 2011), but the interaction between adaptation and plasticity in many of these traits is poorly understood. This has arisen in large part because many previous studies of highland natives have not controlled for the influences of developmental plasticity or adult environment. Furthermore, relatively few studies have examined whether parallel evolution of physiological traits has occurred in independent highland lineages, but there are some examples of uniquely derived traits involved in respiratory and cardiovascular control that have arisen in multiple highland lineages. 3.1. Unique traits of highland taxa Evolved differences in numerous respiratory and cardiovascular traits distinguish highland taxa from their lowland counterparts. Several high-altitude species have been shown to breathe more effectively for O2 transport (McDonough et al., 2006; Brutsaert, 2007; Pichon et al., 2009; Scott, 2011), which should increase the PO2 at the gas-exchange interface (shifting A to D in Fig. 1). For example, plateau pika (Ochotona curzoniae) from the Tibetan plateau breathe using larger tidal volumes and lower breathing frequencies than domestic rats raised at low altitudes when compared at a given total ventilation rate (Pichon et al., 2009). This change in breathing pattern should reduce the contribution of dead space gas to alveolar PO2 and thus increase alveolar ventilation (Fig. 1 D). High-altitude human populations from the Tibetan Plateau and rosy finches (Leucosticte arctoa) native to altitudes above 3500 m in North America also breathe with larger tidal volumes than comparable lowlanders (Clemens, 1988; Beall et al., 1997). Developmental altitude was not controlled in the above studies, but there is some evidence that similar differences persist between highland and lowland natives when compared after being raised in common garden conditions at sea level. Bar-headed geese (Anser indicus), a species that summers on the Tibetan plateau and migrates across the Himalayas breathe with deeper and less frequent breaths than closely-related lowland geese (Scott and Milsom, 2007). Parallel

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changes in breathing pattern have therefore occurred in multiple lineages of high-altitude animals that should improve pulmonary gas exchange in hypoxia. The HVR has also evolved in several highland lineages to change the response of total ventilation to hypoxia. For example, total ventilation in severe poikilocapnic hypoxia is higher in bar-headed geese than in lowland waterfowl when compared after each was raised in similar conditions at sea level (Black and Tenney, 1980a; Scott and Milsom, 2007). In contrast, total ventilation during isocapnic hypoxia is similar between species, suggesting that bar-headed geese have a reduced sensitivity to respiratory hypocapnia that allows breathing to increase by a greater magnitude during environmental hypoxia (in which CO2 levels are uncontrolled) (Scott and Milsom, 2007). Highland human populations from both the Himalayas and Andes also have lower ventilatory sensitivities to CO2 than lowlanders acclimatized to high altitudes as adults (Slessarev et al., 2010a,b). The blunted CO2 chemosensitivity that is observed in multiple highland lineages should minimize the extent to which ventilatory responses to hypocapnia act at cross-purposes to the hypoxic ventilatory response. Whether these consistent modifications in CO2 chemosensitivity are complemented by changes in O2 sensitivity is unclear, because findings have been inconsistent across highland taxa. High-altitude human populations from the Tibetan plateau have high resting ventilation and an increased ventilatory sensitivity to isocapnic hypoxia (Beall, 2000; Moore, 2000; Terblanch et al., 2005; Brutsaert, 2007; Slessarev et al., 2010b). In contrast, human populations from the Andes have low resting ventilation and a blunted response to isocapnic hypoxia compared to Tibetans and lowlanders (Moore, 2000; Brutsaert, 2007; Slessarev et al., 2010b). Although somewhat paradoxical with regards to the needs for oxygen transport at high altitudes, this blunted response could help reduce CO2 loss and help maintain blood CO2/pH homeostasis, or could reduce the energetic costs of breathing (Hochachka, 1986; Powell, 2007). Unfortunately, developmental plasticity was not adequately controlled in many of these human studies, but the available evidence suggests that population genetic background (ancestry) appears to have influenced breathing by altering several time domains of the HVR (e.g., hypoxic desensitization) or the presence and magnitude of developmental plasticity (Brutsaert, 2007). In addition to changes in ventilatory control, multiple high-altitude mammals generally experience little to no pulmonary vasoconstriction and hypertension compared to hypoxia-acclimated lowlanders (Harris et al., 1982; Anand et al., 1986; Durmowicz et al., 1993; Ge et al., 1998; Moore et al., 1998; Pichon et al., 2013). The lack of pulmonary hypertension appears to be an evolved highland trait in at least the yak (Bos grunniens, native to the Himalayas), for which previous studies have compared this highland species to closely-related lowlanders after being raised at a common altitude (Anand et al., 1986). In Tibetan sheep (Ovis ammon), low pulmonary vasoconstriction and arterial pressures is associated with dysfunctional and/or down-regulated Kv channels in the pulmonary artery smooth muscle cells (Ishizaki et al., 2004). Furthermore, very little muscularization is observed in the pulmonary arteries of plateau pika, yaks, llamas, and Tibetan humans (Harris et al., 1982; Durmowicz et al., 1993; Ge et al., 1998; Ishizaki et al., 2004). This is in contrast to the substantial remodelling and muscularization of the pulmonary arterioles in hypoxia-acclimatized rats (Ge et al., 1998). Gasotransmitters such as nitric oxide (NO) and carbon monoxide (CO) are suggested to offset pulmonary vasoconstriction in highland mammals by promoting vasodilation (Kourembanas, 2002; Ndisang and Wang, 2003; Williams et al., 2004). For example, NO synthesis is correlated with pulmonary blood flow in Tibetans (Beall et al., 2001; Hoit et al., 2005; Erzurum et al., 2007), and neonatal llamas (Lama glama) have much higher CO production and hemoxygenase (HO) expression in the lungs than neonatal sheep (Herrera et al., 2008). The reduction in hypoxic pulmonary vasoconstriction in highland animals should minimize the risk of pulmonary oedema and increase the physiological capacity for O2 diffusion, which


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would reduce the lung-arterial PO2 difference (helping shift B to E in Fig. 1). Autonomic regulation of the heart is uniquely altered in many highland taxa, but previous findings are not always consistent. The effects of the sympathetic and parasympathetic nervous systems on heart chronotropic function are blunted in plateau pika raised at high altitudes compared to lowland rats (compared at a common intermediate altitude), in association with reduced expression of β1-adrenoreceptors and M2 muscarinic receptors in the heart (Pichon et al., 2013). Andean guinea pigs also have lower heart rate sensitivity to sympathetic agonists compared to low-altitude lab-strain guinea pigs acclimatized to high altitudes (León-Velarde et al., 1996). In contrast, however, cardiac M2 muscarinic receptor density is increased in highlanders compared to lowland-strain guinea pigs acclimatized to high altitudes (León-Velarde et al., 1996), which is associated with enhanced parasympathetic activity and a lower resting heart rate (Hartley et al., 1974; Hughson et al., 1994; Hopkins et al., 2003). These discrepancies highlight the potential differences between highland taxa, and emphasize that caution must be taken in ascribing adaptive significance to the uniquely-derived traits of highlanders. Nevertheless, the consistent finding of a blunted cardiac sympathetic sensitivity in both of these species could be extremely important for avoiding chronic over-excitation of the heart at high altitudes. The regulation of systemic blood flow in highland taxa is also distinct from that in lowlanders, and includes alterations in the sensitivity of the peripheral vasculature to catecholamines and NO. In adult Himalayan natives, activation of the sympathetic nervous system in response to high-altitude hypoxia is significantly blunted compared to sea-level natives after high-altitude acclimatization (Bernardi et al., 1998). This should minimize α-adrenoreceptor mediated restriction of blood flow in peripheral tissues, and thus increase capillary recruitment and the functional capacity for O2 diffusion (helping shift C to F in Fig. 1). However, fetal and neonatal llamas have increased peripheral vasoconstrictor sensitivity to α-adrenergic stimulation compared to lowland sheep, along with different populations of α1-adrenergic receptor subtypes expressed in the femoral vascular bed (Giussani et al., 1996; Moraga et al., 2011). This unique trait has obvious benefit for coping with short-term reductions in O2 availability in utero, which are likely magnified at high-altitudes, because it should facilitate the redistribution of blood to essential tissues during hypoxia. The benefit of this trait after birth is less clear, because hypoxia is encountered chronically and blood flow to peripheral tissues must resume. It is possible that neonates have temporarily retained the characteristics of fetal llamas, but it is unclear if this trait disappears as development continues. Peripheral blood flow in hypoxia could be maintained in llamas by adaptations that enhance arterial oxygenation and/or reduce sympathetic activation, or by increases in NO-mediated vasodilation. Inhibition of NO synthase increases arterial femoral pressure and total femoral vascular resistance substantially in fetal llamas, suggesting that NO maintains a baseline vasodilatory tone (Sanhueza et al., 2005). NO production is also higher in adult Tibetans in association with enhanced systemic blood flow to peripheral tissues (Erzurum et al., 2007). 3.2. Interactions between adaptation and phenotypic plasticity Studying species across broad altitudinal ranges is a powerful means for understanding the interaction between adaptation and phenotypic plasticity. Species that are restricted to high elevation, such as the llama, plateau pika, and Andean goose, are well-diverged from their closest lowland relatives and are very well suited to elucidating the most extreme highland phenotypes. However, mechanistic studies of population-level variation within broadly distributed species provide the greatest experimental power for elucidating the genetic and environmental sources of phenotypic variation and for distinguishing the evolutionary forces involved (e.g., adaptation, drift, etc.) (Storz et al., 2010).

Evolved differences in transcriptional regulation may underlie the interactions between adaptation and plasticity in indigenous highlanders (Appenzeller et al., 2006; Cheviron et al., 2008, 2013; Storz et al., 2010). For example, population, environment, and population ×environment effects on gene expression have been observed in comparisons of highland and lowland deer mice, and some of this variation is correlated with variation in VO2max and muscle phenotype (Cheviron et al., 2013). The evidence presented in previous sections suggests that both genotypic adaptation and phenotypic plasticity should affect control of breathing and the circulation in high-altitude hypoxia. Future studies that control for the effects of acclimation, development, and ancestry are needed to fully appreciate the genetic and environmental contributions to the high-altitude phenotype. 4. Conclusions and perspectives Bill Milsom made a career of studying respiratory and cardiovascular control in a range of vertebrates. As he states, “The literature is rich with the details of comparative studies of respiratory structure and function that outline the diversity of existing solutions to the different sets of constraints imposed on different species. There is far less known about the mechanisms controlling these functional processes” (Milsom, 2010). Even less is known about how these mechanisms evolve, but the emerging story in high-altitude mammals and birds suggests that oxygen transport can be at least partially maintained in hypoxia by evolved changes in respiratory and cardiovascular control. Parallel evolution of some of these changes in independent highland lineages lends support to their potential adaptive significance (Projecto-Garcia et al., 2013). However, in some instances, independent highland lineages have evolved different functional solutions to the same problem (Beall, 2007). Many fascinating questions remain about the genomic basis of high-altitude adaptation (Cheviron and Brumfield, 2012) and the importance of adaptation, acclimatization, developmental plasticity, and transgenerational transfer in highland natives. References Ågren, P., Cogolludo, A.L., Kessels, C.G., Pérez-Vizcaíno, F., De Mey, J.G., Blanco, C.E., Villamor, E., 2007. Ontogeny of chicken ductus arteriosus response to oxygen and vasoconstrictors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R485–R496. Anand, I.S., Harris, E., Ferrari, R., Pearce, P., Harris, P., 1986. Pulmonary haemodynamics of the yak, cattle, and cross breeds at high altitude. Thorax 41, 696–700. Appenzeller, O., Minko, T., Qualls, C., Pozharov, V., Gamboa, J., Gamboa, A., Wang, Y., 2006. Gene expression, autonomic function and chronic hypoxia: lessons from the Andes. Clin. Auton. Res. 16, 217–222. Archer, S.L., London, B., Hampl, V., Wu, X.C., Nsair, A., Puttagunta, L., Hashimoto, K., Waite, R.E., Michelakis, E.D., 2001. Impairment of hypoxic pulmonary vasoconstriction in mice lacking the voltage-gated potassium channel Kv1.5. FASEB J. 15, 1801–1803. Banchero, N., 1987. Cardiovascular responses to chronic hypoxia. Annu. Rev. Physiol. 49, 465–476. Barnard, P., Andronikou, S., Pokorski, M., Smatresk, N., Mokashi, A., Lahiri, S., 1987. Timedependent effect of hypoxia on carotid body chemosensory function. J. Appl. Physiol. 63, 685–691. Bavis, R.W., 2005. Developmental plasticity of the hypoxic ventilatory response after perinatal hyperoxia and hypoxia. Respir. Physiol. Neurobiol. 149, 287–299. Bavis, R.W., Mitchell, G.S., 2008. Long-term effects on the perinatal environment on respiratory control. J. Appl. Physiol. 104, 1220–1229. Bavis, R.W., Olson Jr., E.B., Vidruk, E.H., Fuller, D.D., Mitchell, G.S., 2004. Developmental plasticity of the hypoxic ventilatory response in rats induced by neonatal hypoxia. J. Physiol. 557, 645–660. Bayliss, D.A., Millhorn, D.E., Gallman, E.A., Cidlowski, J.A., 1987. Progesterone stimulates ventilation through a central nervous system steroid receptor-mediated mechanism in the cat. Proc. Natl. Acad. Sci. U. S. A. 84, 7788–7792. Beall, C.M., 2000. Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum. Biol. 72, 201–228. Beall, C.M., 2007. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc. Natl. Acad. Sci. 104 (S1), 8655–8660. Beall, C.M., Strohl, K.P., Blangero, J., Williams-Blangero, S., Almasy, L.A., Decker, M.J., Worthman, C.M., Goldstein, M.C., Vargas, E., Villena, M., Soria, R., Alarcon, A.M., Gonzales, C., 1997. Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives. Am. J. Phys. Anthropol. 104, 427–447. Beall, C.M., Laskowski, D., Strohl, K.P., Soria, R., Villena, M., Vagras, E., Alacron, A.M., Gonzales, C., Erzurum, S.C., 2001. Pulmonary nitric oxide in mountain dwellers. Nature 414, 411–412.


C.M. Ivy, G.R. Scott / Comparative Biochemistry and Physiology, Part A xxx (2014) xxx–xxx Bernardi, L., Passino, C., Spadacini, G., Calciati, A., Robergs, R., Greene, R., Martignoni, E., Anand, I., Appenzeller, O., 1998. Cardiovascular autonomic modulation and activity of carotid barorreceptors at altitude. Clin. Sci. 95, 563–573. Bernardo, J., 1996. The particular maternal effect of propagule size, especially egg size: patterns, models, quality of evidence and interpretations. Am. Zool. 36, 216–236. Black, C.P., Tenney, S.M., 1980a. Oxygen transport during progressive hypoxia in high altitude and sea level waterfowl. Respir. Physiol. 39, 217–239. Black, C.P., Tenney, S.M., 1980b. Pulmonary hemodynamic responses to acute and chronic hypoxia in two waterfowl species. Comp. Biochem. Physiol. 67A, 291–293. Blauw, G.J., Westendorp, R.G.J., Simons, M., Chang, P.C., Frölich, M., Meinders, A.E., 1995. β-Adrenergic receptors contribute to hypoxaemia induced vasodilation in man. Br. J. Clin. Pharmacol. 40, 453–458. Boutilier, R.G., 2001. Mechanisms of cell survival in hypoxia and hypothermia. J. Exp. Biol. 204, 3171–3181. Briana, D.D., Malamitsi-Puchner, A., 2009. Intrauterine growth restriction and adult disease: the role of adipocytokines. Eur. J. Endocrinol. 160, 337–347. Brooks, J.G., Tenney, S.M., 1968. Ventilatory response of llama to hypoxia at sea level and high altitude. Respir. Physiol. 5, 269–278. Brutsaert, T.D., 2007. Population genetic aspects and phenotypic plasticity of ventilatory responses in high altitude natives. Respir. Physiol. Neurobiol. 158, 151–160. Bureau, M., Bouverot, P., 1975. Blood and CSF acid-base changes, and rate of ventilatory acclimatization of awake dogs to 3,550 m. Respir. Physiol. 24, 203–216. Burton, T., Metcalfe, N.B., 2014. Can environmental conditions experienced in early life influence future generations? Proc. R. Soc. B 281, 1–8. Calbet, J.A., 2003. Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans. J. Physiol. 551, 379–386. Carroll, J.L., Bamford, O.S., Fitzgerald, R.S., 1993. Postnatal maturation of carotid chemoreceptor responses to O2 and CO2 in the cat. J. Appl. Physiol. 75, 2383–2391. Cheviron, Z.A., Brumfield, R.T., 2012. Genomic insights into adaptation to high-altitude environments. Heredity 108, 354–361. Cheviron, Z.A., Whitehead, A., Brumfield, R.T., 2008. Transcriptomic variation and plasticity in rufous-collared sparrows (Zonotrichia capensis) along an altitudinal gradient. Mol. Ecol. 17, 4556–4569. Cheviron, Z.A., Connaty, A.D., McClelland, G.B., Storz, J.F., 2013. Functional genomics of adaptation to hypoxic cold-stress in high-altitude deer mice: transcriptomic plasticity and thermogenic performance. Evolution 68, 48–62. Clemens, D.T., 1988. Ventilation and oxygen consumption in rosy finches and house finches at sea level and high altitude. J. Comp. Physiol. B. 158, 57–66. Coney, A.M., Bishay, M., Marshall, J.M., 2004. Influence of endogenous nitric oxide on sympathetic vasoconstriction in normoxia, acute and chronic systemic hypoxia in the rat. J. Physiol. 555, 793–804. Darnaudéry, M., Maccari, S., 2008. Epigenetic programming of stress response in male and female rats by prenatal restraint stress. Brain Res. Rev. 57, 571–585. Dhar, P., Sharma, V.K., Hota, K.B., Das, S.K., Hota, S.K., Srivastava, R.B., Singh, S.B., 2014. Autonomic cardiovascular responses in acclimatized lowlanders on prolonged stay at high altitude: a longitudinal follow up study. PLoS One 9, e84274. Dinenno, F.A., Joyner, M.J., Halliwill, J.R., 2003. Failure of systemic hypoxia to blunt α-adrenergic vasoconstriction in the human forearm. J. Physiol. 549, 985–994. Duffin, J., Mahamed, S., 2003. Adaptation in the respiratory control system. Can. J. Physiol. 81, 765–773. Durmowicz, A.G., Hofmeister, S., Kadyraliev, T.K., Aldashev, A.A., Stenmark, K.R., 1993. Functional and structural adaptation of the yak pulmonary circulation to residence at high altitude. J. Appl. Physiol. 74, 2276–2285. Dwinell, M.R., Powell, F.L., 1999. Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anaesthetized rats. J. Appl. Physiol. 87, 817–823. Dwinell, M.R., Janssen, P.L., Pizarro, J., Bisgard, G.E., 1997. Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia. J. Appl. Physiol. 82, 118–124. Dzialowski, E.M., Reed, W.L., Sotherland, P.R., 2009. Effects of egg size on double-crested cormorant (Phalacrocorax auritus) egg composition and hatchling phenotype. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 152, 262–267. Eden, G.J., Hanson, M.A., 1987. Effects of chronic hypoxia from birth on the ventilatory response to acute hypoxia in the newborn rat. J. Physiol. 392, 11–19. Eldridge, M.W., Braun, R.K., Yoneda, K.Y., Walby, W.F., 2006. Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema. J. Appl. Physiol. 100, 972–980. Erzurum, S.C., Ghosh, S., Janocha, A.J., Xu, W., Bauer, S., Bryan, N.S., Tejero, J., Hemann, C., Hille, R., Stuehr, D.J., Feelisch, M., Beall, C.M., 2007. Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proc. Natl. Acad. Sci. U. S. A. 104, 17593–17598. Evans, M.A., Ward, J.P., 2009. Hypoxic pulmonary vasoconstriction. Adv. Exp. Med. Biol. 648, 351–360. Faraci, F.M., Kilgore, D.L., Fedde, M.R., 1984. Attenuated pulmonary pressure response to hypoxia in bar-headed geese. Am. J. Physiol. 247, R402–R403. Fatemian, M., Robbins, P.A., 1998. Human ventilatory response to CO2 after 8 h of isocapnic or poikilocapnic hypoxia. J. Appl. Physiol. 85, 1922–1928. Finkler, M.S., Van Orman, J.B., Sotherland, P.R., 1998. Experimental manipulation of egg quality in chickens: influence of albumen and yolk on the size and body composition of near-term embryos in precocial bird. J. Comp. Physiol. B. 168, 17–24. Foster, G.E., Ainslie, P.N., Stembridge, M., Day, T.A., Bakker, A., Lucas, S.J.E., Lewis, N.C.S., MacLeod, D.B., Lovering, A.T., 2014. Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas. J. Physiol. 592 (13997-1409). Ge, R., Kubo, K., Kobayashi, T., Sekiguchi, M., Honda, T., 1998. Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude. Am. J. Physiol. 274, H1792–H1799.

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Giussani, D.A., Riuelme, R.A., Moraga, F.A., McGarrigle, H.H.G., Gaete, C.R., Sanhueza, E.M., Hanson, M.A., Llanos, A.J., 1996. Chemoreflex and endocrine components of cardiovascular responses to acute hypoxemia in the llama fetus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 271, R73–R83. Gleed, R.D., Mortola, J.P., 1991. Ventilation in newborn rats after gestation at simulated high altitude. J. Appl. Physiol. 70, 1146–1151. Gonzalez, N.C., Clancy, R.L., Wagner, P.D., 1993. Determinants of maximal oxygen uptake in rats acclimated to simulated altitude. J. Appl. Physiol. 75, 1608–1614. Gonzalez, C., Almaraz, L., Obeso, A., Rigual, R., 1994. Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol. Rev. 74, 829–898. Graf, A.V., Maslova, M.V., Maklakova, A.S., Sokolova, N.A., Kudryashova, N.Y., Krushinskaya, Y.V., Goncharenko, E.N., Neverova, M.E., Fidelina, O.V., 2006. Effect of hypoxia during early organogenesis on cardiac activity and noradrenergic regulation in the postnatal period. Bull. Exp. Biol. Med. 142, 543–545. Groothuis, T.G., Müller, W., von Engelhardt, N., Carere, C., Eising, C., 2005. Maternal hormones as a tool to adjust offspring phenotype in avian species. Neurosci. Biobehav. Rev. 29, 329–352. Hainsworth, R., Drinkhill, M.J., 2007. Cardiovascular adjustments for life at high altitude. Respir. Physiol. Neurobiol. 158, 204–211. Hainsworth, R., Drinkhill, M.J., Rivera-Chira, M., 2007. The autonomic nervous system at high altitude. Clin. Auton. Res. 17, 13–19. Halliwill, J.R., 2003. Hypoxic regulation of blood flow in humans: Skeletal muscle circulation and the role of epinephrine. Adv. Exp. Med. Biol. 543, 223–236. Harris, P., Heath, D., Smith, P., Willilams, D., Ramirez, A., Krüger, H., Jones, D.M., 1982. Pulmonary circulation of the llama at high and low altitudes. Thorax 37, 38–45. Hartley, L.H., Vogel, J.A., Cruz, J.C., 1974. Reduction of maximal exercise heart rate at altitude and its reversal with atropine. J. Appl. Physiol. 36, 362–365. Hawkes, L.A., Balachandran, S., Batbayar, N., Butler, P.J., Chua, B., Douglas, D.C., Frappell, P.B., Hou, Y., Milsom, W.K., Newman, S.H., Prosser, D.J., Sathiyaselvam, P., Scott, G.R., Takekawa, J.Y., Natsagdorj, T., Wikelski, M., Witt, M.J., Yan, B., Bishop, C.M., 2013. The paradox of extreme high-altitude migration in bar-headed greese Anser indicus. Proc. R. Soc. B 280, 1–9. Haxhiu, M.A., Chang, C.H., Dreshaj, I.A., Erokwu, B., Prabhakar, N.R., Cherniack, N.S., 1995. Nitric oxide and ventilatory response to hypoxia. Respir. Physiol. 101, 257–266. Heath, D., Edwards, C., Winson, M., Smith, P., 1973. Effects on the right ventricle, pulmonary vasculature, and carotid bodies of the rat of exposure to, and recovery from, simulated high altitude. Thorax 28, 24–28. Hempleman, S.C., 1995. Sodium and potassium currents in neonatal rat carotid body cells following in vivo chronic hypoxia. Brain Res. 699, 42–50. Hempleman, S.C., 1996. Increased calcium currents in carotid body glomus cells following in vivo acclimatization to chronic hypoxia. J. Neurophysiol. 76, 1880–1886. Herrera, E.A., Pulgar, V.M., Riquelme, R.A., Sanhueza, E.M., Reyes, R.V., Ebensperger, G., Parer, J.T., Valdéz, E.A., Giussani, D.A., Blanco, C.E., Hanson, M.A., Llanos, A.J., 2007. High-altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R2234–R2240. Herrera, E.A., Reyes, R.V., Giussani, D.A., Riquelme, R.A., Sanhueza, E.M., Ebensperger, G., Casanello, P., Méndez, N., Ebensperger, R., Sepúlveda-Kattan, E., Pulgar, V.M., Cabello, G., Blanco, C.E., Hanson, M.A., Parer, J.T., Llanos, A.J., 2008. Carbon monoxide: a novel pulmonary artery vasodilator in neonatal llamas of the Andean altiplano. Cardiovasc. Res. 77, 197–201. Herrera, E.A., Riquelme, R.A., Ebensperger, G., Reyes, R.V., Ulloa, C.E., Cabello, G., Krause, B.J., Parer, J.T., Giussani, D.A., Llanos, A.J., 2010. Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R1676–R1684. Hertzberg, T., Hellström, S., Lagercrantz, H., Pequignot, J.M., 1990. Development of the arterial chemoreflex and turnover of carotid body catecholamines in the newborn rat. J. Physiol. Lond. 425, 211–225. Hill, C.B., Grandgeorge, S.H., Bavis, R.W., 2013. Developmental hyperoxia alters CNS mechanisms underlying hypoxic ventilatory depression in neonatal rats. Respir. Physiol. Neurobiol. 189, 498–505. Ho, D.H., Burggren, W.W., 2010. Epigenetics and transgenerational transfer: a physiological perspective. J. Exp. Biol. 213, 3–16. Ho, D.H., Burggren, W.W., 2012. Parental hypoxic exposure conters offspring hypoxia resistance in zebrafish (Danio rerio). J. Exp. Biol. 215, 4208–4216. Hochachka, P.W., 1986. Defense strategies against hypoxia and hypothermia. Science 231, 234–241. Hoit, B.D., Dalton, N.D., Erzurum, S.C., laskowski, D., Strohl, K.P., Beall, C.M., 2005. Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders. J. Appl. Physiol. 99, 1796–1801. Hong, Z., Weir, E.K., Nelson, D.P., Olschewski, A., 2004. Subacute hypoxia decreases voltage-activated potassium channel expression and function in pulmonary artery myocytes. Am. J. Respir. Cell Mol. Biol. 31, 337–343. Hopkins, S.R., Bogaard, H.F., Niizeki, K., Yamaya, Y., Ziegler, M.G., Wagner, P.D., 2003. Betaadrenergic or parasympathetic inhibition, heart rate and cardiac output during normoxic and acute hypoxic exercise in humans. J. Physiol. 550, 605–616. Hsia, C.C.W., Carbayo, J.J.P., Yan, X., Bellotto, D.J., 2005. Enhanced alveolar growth and remodelling in Guinea pigs raised at high altitude. Respir. Physiol. Neurobiol. 147, 105–115. Hsia, C.C.W., Johnson, R.L., McDonough, R., Dane, D.M., Hurst, M.D., Fehmel, J.L., Wagner, H.E., Wagner, P.D., 2007. Residence at 3,800 m altitude for 5 mo in growing dogs enhances lung diffusion capacity for oxygen that persists at least 2.5 years. J. Appl. Physiol. 102, 1448–1455. Hughson, R.L., Yamamoto, Y., McCullough, R.E., Sutton, J.R., Reeves, J.T., 1994. Sympathetic and parasympathetic indicators of heart rate control at altitude studied by spectral analysis. J. Appl. Physiol. 77, 2537–2542.


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Ishizaki, T., Sakai, A., Koizumi, T., Ruan, Z., Wang, Z.G., 2004. Blunted effect of the Kv channel inhibitor on pulmonary circulation in Tibetan sheep: A model for studying hypoxia and pulmonary artery pressure regulation. Respirology 9, 125–129. Iversen, N.K., Wang, T., Baatrup, E., Crossley, D.A., 2014. The role of nitric oxide in the cardiovascular response to chronic and acute hypoxia in White Leghorn chicken (Gallus domesticus). Acta Physiol. 211, 346–357. Jablonka, E., Raz, G., 2009. Transgenerational epigenetic inheritance: Prevalence, mechanisms, and implications for the study of heredity and evolution. Q. Rev. Biol. 84, 131–176. Jacob, E., Drexel, M., Schwerte, T., Pelster, B., 2002. Influence of hypoxia and of hypoxemia on the development of cardiac activity in zebrafish larvae. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R911–R917. Jones, R.D., Morice, A.H., Emery, C.J., 2004. Effects of perinatal exposure to hypoxia upon the pulmonary circulation of the adult rat. Physiol. Res. 53, 11–17. Joseph, V., Soliz, J., Soria, R., Pequignot, J., Favier, R., Spielvogel, H., Pequignot, J.M., 2002. Dopaminergic metabolism in carotid bodies and high altitude acclimation in female rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R765–R773. Kacimi, R., Richalet, J.P., Corsin, A., Abousahl, I., Crozatier, B., 1992. Hypoxia-induced downregulation of beta-adrenergic receptors in rat heart. J. Appl. Physiol. 73, 1377–1382. Kacimi, R., Richalet, J.P., Crozatier, B., 1993. Hypoxia-induced differential modulation of adenosinergic and muscarinic receptors in rat heart. J. Appl. Physiol. 75, 1123–1128. Kappeler, L., Meaney, M.J., 2010. Epigenetics and parental effects. Bioessays 32, 818–827. Kourembanas, S., 2002. Hypoxia and carbon monoxide in the vasculature. Antioxid. Redox Signal. 4, 291–299. Kumar, P., Prabhakar, N., 2012. Peripheral chemoreceptors: function and plasticity of the carotid body. Compr. Physiol. 2, 141–219. Kusakabe, T., Powell, F.L., Ellisman, M.H., 1993. Ultrastructure of the glomus cells in the carotid body of chronically hypoxic rats: with special reference to the similarity of amphibian glomus cells. Anat. Rec. 237, 220–227. León-Velarde, F., Sanchez, J., Bigard, A.X., Brunet, A., Lesty, C., Monge, C., 1993. High altitude tissue adaptation in Andean coots: capillarity, fiber area, fiber type and enzymatic activities of skeletal muscle. J. Comp. Physiol. B. 163, 52–58. León-Velarde, F., Richalet, J.P., Chavez, J., Kacimi, R., Rivera-Ch, M., Palacios, J., Clark, D., 1996. Hypoxia and normoxia induced reversibility of autonomic control in Andean guinea pig heart. J. Appl. Physiol. 81, 2229–2234. León-Velarde, F., Bourin, M.C., Germack, R., Mohammadi, K., Crozatier, B., Richalet, J.P., 2001a. Differential alterations in cardiac adrenergic signalling in chronic hypoxia or norepinephrine infusion. Am. J. Physiol. 280, R274–R281. León-Velarde, F., Rivera-Chira, M., Tapia, R., Huicho, L., Monge, C.C., 2001b. Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R488–R493. Light, K.E., Dick, T.E., Hughes, M.J., 1984. Central and peripheral receptors in guinea pig exposed to simulated high altitude. Neuropharmacology 23, 189–195. Lovering, A.T., Romer, L.M., Haverkamp, H.C., Pegelow, D.F., Hokanson, J.S., Eldridge, M.W., 2008. Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans. J. Appl. Physiol. 104, 1418–1425. Lumbroso, D., Joseph, V., 2009. Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R421–R427. Lumbroso, D., Lemoine, A., Gonzalez, M., Villalpando, G., Seaborn, T., Joseph, V., 2012. Lifelong consequences of postnatal normoxia exposure in rats raised at high altitude. J. Appl. Physiol. 112, 33–41. Maggiorini, M., Melot, C., Pierre, S., Pfeiffer, F., Greve, I., Sartori, C., Lepori, M., Hauser, M., Scherrer, U., Naeije, R., 2001. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 103, 2078–2083. Markwald, R.R., Kirby, B.S., Crecelius, A.R., Carlson, R.E., Voyles, W.F., Dinenno, F.A., 2011. Combined inhibition of nitric oxide and vasodilating prostagladins abolishes forearm vasodilatino to systemic hypoxia in healthy humans. J. Physiol. 589, 1979–1990. Marshall, J.M., 1994. Peripheral chemoreceptors and cardiovascular regulation. Physiol. Rev. 74, 543–594. Mastorci, F., Vicentini, M., Viltart, O., Manghi, M., Graiani, G., Quaini, F., Meerio, P., Nalivaiko, E., Macarri, S., Sgoifo, A., 2009. Long-term effects of prenatal stress: changes in adult cardiovascular regulation and sensitivity to stress. Neurosci. Biobehav. Rev. 33, 191–203. Mathieu-Costello, O., Agey, P.J., Wu, L., Szewczak, J.M., MacMillen, R.E., 1998. Increased fiber capillarization in flight muscle of finch at altitude. Respir. Physiol. 111, 189–199. Mazzeo, R.S., Wolfel, E.E., Butterfield, G.E., Reeves, J.T., 1994. Sympathetic response during 21 days at high altitude (4,300 m) as determined by urinary and arterial catecholarmines. Metabolism 10, 1226–1232. McDonough, P., Dane, D.M., Hsia, C.C.W., Yilmaz, C., Johnson, R.L., 2006. Long-term enhancement of pulmonary gas exchange after high-altitude residence during maturation. J. Appl. Physiol. 100, 474–480. Milsom, W.K., 2010. Adaptive trends in respiratory control: a comparative perspective. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R1–R10. Monge, C., León-Velarde, F., 1991. Physiological adaptation to high altitude:oxygen transport in mammals and birds. Physiol. Rev. 71, 1135–1172. Moore, L.G., 2000. Comparative human ventilatory adaptation to high altitude. Respir. Physiol. 121, 257–276. Moore, L.G., Niermeyer, S., Zamudio, S., 1998. Human adaptation to high altitude: regional and life-cycle perspectives. Am. J. Phys. Anthropol. 27, 25–64. Moraga, F.A., Reyes, R.V., Herrera, E.A., Riquelme, R.A., Ebensperger, G., Pulgar, V.M., Parer, J.R., Giussani, D.A., Llanos, A.J., 2011. Role of the α-adrenergic system in femoral vascular reactivity in neonatal llamas and sheep: a comparative study between highland and lowland species. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1153–R1160. Morel, O.E., Buvry, A., Le Corvoisier, P., Tual, L., Favret, F., León-Velarde, F., Crozetier, B., Richalet, J.P., 2003. Effects of nifedipine-induced pulmonary vasodilation on cardiac

receptors and protein kinase C isoforms in the chronically hypoxic rat. Pflugers Arch. 446, 356–364. Moudgil, R., Michelakis, E.D., Archer, S.L., 2005. Hypoxic pulmonary vasoconstriction. J. Appl. Physiol. 98, 390–403. Naeije, R., Dedobbeleer, C., 2013. Pulmonary hypertension and the right ventricle in hypoxia. Exp. Physiol. 98, 1247–1256. Nakanishi, K., Tajima, F., Osada, H., Nakamura, A., Yagura, S., Kawai, T., Suzuki, M., Torikata, C., 1996. Pulmonary, vascular responses in rats exposed to chronic hypobaric hypoxia at two different altitude levels. Pathol. Res. Pract. 192, 1057–1067. Ndisang, J.F., Wang, R., 2003. Alterations in heme oxygenaseécarbon monoxide system in pulmonary arteries in mypertension. Exp. Biol. Med. 228, 557–563. Nikinmaa, M., 2001. Haemoglobin function in vertebrates: evolutionary changes in cellular regulation in hypoxia. Respir. Physiol. 128, 317–329. Nurse, C.A., 2010. Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors. Exp. Physiol. 95, 657–667. Okubo, S., Mortola, J.P., 1990. Control of ventilation in adult rats hypoxic in the neonatal period. Am. J. Physiol. 259, R836–R841. Olson, K.R., Dombkowski, R.A., Russell, M.J., Doellman, M.M., Head, S.K., Whitfield, N.L., Madden, J.A., 2006. Hydrogen sulphide as an oxygen sensor/transducer in vertebrate hypoxic vasoconstriction and hypoxic vasodilation. J. Exp. Biol. 209, 4011–4023. Pamenter, M.E., Carr, J.A., Go, A., Fu, Z., Reid, S.G., Powell, F.L., 2014. Glutamate receptors in the nucleus tractus solitarius contribute to ventilatory acclimatization to hypoxia in rat. J. Physiol. 592, 1839–1856. Papamatheakis, D.G., Blood, A.B., Kim, J.H., Wilson, S.M., 2013. Antenatal hypoxia and pulmonary vascular function and remodeling. Curr. Vasc. Pharmacol. 11, 616–640. Pardal, R., Ortega-Saenz, P., Duran, R., Lopex-Barneo, J., 2007. Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell 131, 364–377. Peyronnet, J., Roux, J.C., Géloën, A., Tang, L.Q., Pequignot, J.M., Lagercrantz, H., Dalmaz, Y., 2000. Prenatal hypoxia impairs the postnatal development of neural and functional chemoafferent pathway in rat. J. Physiol. 542, 525–537. Peyronnet, J., Dalmaz, Y., Ehrström, M., Mamet, J., Roux, J.C., Pequignot, J.M., Thorén, H.P., Lagercrantz, H., 2002. Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats. Pflugers Arch. 443, 858–865. Peyronnet, J., Roux, J.C., Mamet, J., Perrin, D., Lachuer, J., Pequignot, J.M., Dalmaz, Y., 2007. Developmental plasticity of the carotid chemoafferent pathway in rats that are hypoxic during the prenatal period. Eur. J. Neurosci. 26, 2865–2872. Pichon, A., Zhenzhong, B., Favret, F., Jin, G., Shufeng, H., Marchant, D., Richalet, J., Ge, R., 2009. Long-term ventialtory adaptation and ventilatory response to hypoxia in plateau pika (Ochotona curzoniae): role of nNOS and dopamine. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R978–R987. Pichon, A., Zhenzhong, B., Marchant, D., Jin, G., Voituron, N., Haixia, Y., Favret, F., Richalet, J., Ge, R., 2013. Cardiac adaptation to high altitude in the plateau pika (Ochotona curzoniae). Physiol. Rep. 1, 1–9. Piskuric, N.A., Nurse, C.A., 2013. Expanding role of ATP as a versatile messenger at carotid and aortic body chemoreceptors. J. Physiol. 591, 415–422. Powell, F.L., 2007. The influence of chronic hypoxia upon chemoreception. Respir. Physiol. Neurobiol. 157, 154–161. Powell, F.L., Fu, Z., 2008. HIF-1 and ventilatory acclimatization to chronic hypoxia. Respir. Physiol. Neurobiol. 164, 282–287. Powell, F.L., Hasting, R.H., Mazzone, R.W., 1985. Pulmonary vascular resistance during unilateral pulmonary artery occlusion in ducks. Am. J. Physiol. 249, R39–R43. Powell, F.L., Milson, W.K., Mitchell, G.S., 1998. Time domains of the hypoxic ventilatory response. Respir. Physiol. 112, 123–134. Powell, F.L., Dwinell, M.R., Aaron, E.A., 2000a. Measuring ventilatory acclimatization to hypoxia: Comparative aspects. Respir. Physiol. 122, 271–284. Powell, F.L., Huey, K.A., Dwinell, M.R., 2000b. Central nervous system mechanisms of ventilatory acclimatization to hypoxia. Respir. Physiol. 121, 223–236. Powell, F.L., Shams, H., Hempleman, S.C., Mitchell, G.S., 2004. Breathing in thin air: acclimatization to altitude in ducks. Respir. Physiol. Neurobiol. 144, 225–235. Prabhakar, N.R., 2013. Sensing hypoxia: physiology, genetics and epigenetics. J. Physiol. 591, 2245–2257. Prabhakar, N.R., Jacono, F.J., 2005. Cellular and molecular mechanisms associated with carotid body adaptations to chronic hypoxia. High Alt. Med. Biol. 6, 112–121. Projecto-Garcia, J., Natarajan, C., Moriyama, H., Weber, R.E., Fago, A., Cheviron, Z.A., Dudley, R., McGuire, J.A., Witt, C.C., Storz, J.F., 2013. Repeated elevational transitions in hemoglobin function during the evolution of Andean hummingbirds. Proc. Natl. Acad. Sci. 110, 20669–20674. Ravikumar, P., Bellotto, D.J., Johnson, R.L., Hsia, C.C., 2009. Permanent remodelling in canine lung induced by high-altitude residence during maturation. J. Appl. Physiol. 107, 1911–1917. Reeves, J.T., Groves, B.M., Sutton, J.T., Wagner, P.D., Cymerman, A., Malconian, M.K., Rock, P.D., Young, P.M., Houston, C.S., 1987. Operation Everest II: preservation of cardiac function at extreme altitude. J. Appl. Physiol. 63, 531–539. Reid, S.G., Powell, F.L., 2005. Effects of chronic hypoxia on MK-801-induced changes in the acute hypoxic ventilatory response. J. Appl. Physiol. 99, 2108–2114. Reis, D.J., Golanov, E.V., Ruggiero, D.A., Sun, M.K., 1994. Sympathoexcitatory neurons of the rostal ventrolateral medulla are oxygen sensors and essential elements in the tonic and reflex control of the systemic and cerebral circulations. J. Hypertens. Suppl. 12, S159–S180. Richalet, J.P., Le-Trong, J.L., Rathat, C., Merlet, P., Bouissou, P., Keromes, A., Veyrac, P., 1989. Reversal of hypoxia-induced decrease in human cardiac response to isoproterenol infusion. J. Appl. Physiol. 67, 523–527. Richalet, J.P., Kacimi, R., Antezana, A.M., 1992. The control of cardiac chronotropic function in hypobaric hypoxia. Int. J. Sports Med. 13, S22–S24.


C.M. Ivy, G.R. Scott / Comparative Biochemistry and Physiology, Part A xxx (2014) xxx–xxx Ruijtenbeek, K., le Noble, F.A., Janssen, G.M., Kessels, C.G., Fazzi, G.E., Blanco, C.E., De Mey, J.G., 2000. Chronic hypoxia stimulates periarterial sympathetic nerve development in chicken embryo. Circulation 102, 2892–2897. Ruijtenbeek, K., Kessels, C.G., Janssen, B.J., Bitsch, N.J., Fazzi, G.E., Janssen, G.M., De Mey, J., Blanco, C.E., 2003. Chronic moderate hypoxia during in ovo development alters arterial reactivity in chickens. Pflugers Arch. 447, 158–167. Sanhueza, E.M., Riquelme, R.A., Herrera, E.A., Giussani, D.A., Blanco, C.E., Hanson, M.A., Llanos, A.J., 2005. Vasodilator tone in the llama fetus: the role of nitric oxide during normoexmia and hypoxemia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R776–R783. Scott, G.R., 2011. Elevated performance: the unique physiology of birds that fly at high altitudes. J. Exp. Biol. 214, 2455–2462. Scott, G.R., Milsom, W.K., 2007. Control of breathing and adaptation to high altitude in the bar-headed goose. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R379–R391. Scott, G.R., Milsom, W.K., 2009. Control of breathing in birds: Implications for high altitude flight. In: Glass, M.L., Wood, S.C. (Eds.), Cardio-respiratory control in vertebrates: comparative and evolutionary aspects. Springer-Verlag, Berlin, pp. 429–448. Scott, G.R., Egginton, S., Richards, J.G., Milson, W.K., 2009. Evolution of muscle phenotype for extreme high altitude flight in the bar-headed goose. Proc. R. Soc. Lond. B Biol. Sci. 276, 3645–3653. Scott, G.R., Meir, J.U., Hawkes, L.A., Frappell, P.B., Milsom, W.K., 2011. Point: high altitude is for the birds! J. Appl. Physiol. 111, 1514–1515. Sizlan, A., Ogur, R., Ozer, M., Irmak, M.K., 2008. Blood pressure changes in young male subjects exposed to a median altitude. Clin. Auton. Res. 18, 84–89. Slessarev, M., Mardimae, A., Preiss, D., Vesely, A., Balaban, D.Y., Greene, R., Duffin, J., Fisher, J.A., 2010a. Differences in the control of breathing between Andean highlanders and lowlanders after 10 days acclimatization at 3850 m. J. Physiol. 588, 1607–1621. Slessarev, M., Prisman, E., Ito, S., Watson, R.R., Jensen, D., Preiss, D., Greene, R., Noroboo, T., Stobdan, T., Diskit, D., Norboo, A., Kunzang, M., Appenzeller, O., Duffin, J.J., Fisher, J.A., 2010b. Differences in the control of breathing between Himalayan and sea-level residents. J. Physiol. 588, 1591–1606. Slingo, M.E., Turner, P.J., Christian, H.C., Buckler, K.J., Robbins, P.A., 2014. The von HippelLindau Chuvash mutation in mice causes carotid-body hyperplasia and enhanced ventilatory sensitivity to hypoxia. J. Appl. Physiol. 116, 885–892. Somlyo, A.P., Somlyo, A.V., 1994. Signal transduction and regulation in smooth muscle. Nature 372, 231–236. Sterni, L.M., Bamford, O.S., Wasicko, M.J., Carroll, J.L., 1999. Chronic hypoxia abolished the postnatal increase in carotid body type I cell sensitivity to hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 227, L645–L652. Storz, J.F., Moriyama, H., 2008. Mechanisms of hemoglobin adaptation to high-altitude hypoxia. High Alt. Med. Biol. 9, 148–157. Storz, J.F., Scott, G.R., Cheviron, Z.A., 2010. Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J. Exp. Biol. 213, 4125–4136. Szdzuy, K., Mortola, J.P., 2007. Ventilatory chemosensitivity of the 1-day-old chicken hatchling after embryonic hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1640–R1649. Taylor, C.R., Weibel, E.R., 1981. Design of the mammalian respiratory system. I. Problem and strategy. Respir. Physiol. 44, 1–10.

9

Teppema, L.J., Dahan, A., 2010. The ventilatory responses to hypoxia in mammals: mechanisms, measurement, and analysis. Physiol. Rev. 90, 675–754. Terblanch, J.S., Tolley, K.A., Fahlman, A., Myburgh, K.A., Jackson, S., 2005. The acute hypoxic ventilatory response: Testing the adaptive significance in human populations. Comp. Biochem. Physiol. 140, 349–362. Vieau, D., Sebaai, N., Léonhardt, M., Dutriez-Casteloot, I., Molendi-Coste, O., Laborie, C., Breton, C., Deloof, S., Lesage, J., 2007. HPA axis programming by maternal undernutrition in the male rat offspring. Psychoneuroendocrino 32, S16–S20. Vizek, M., Pickett, C.K., Weil, J.V., 1987. Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia. J. Appl. Physiol. 63, 2403–2410. Voelkel, N.F., Hegstrand, L., Reeves, J.T., McMurty, I.F., Molinoff, P.B., 1981. Effects of hypoxia on density of beta-adrenergic receptors. J. Appl. Physiol. 50, 363–366. Vogel, J.A., Harris, C.W., 1967. Cariopulmonary responses of resting man during early exposure to high altitude. J. Appl. Physiol. 22, 1124–1128. Wang, J., Juhaszova, M., Rubin, L.J., Yuan, X.J., 1997. Hypoxia inhibits gene expression of voltage-gated K+ channel α subunits in pulmonary artery smooth muscle cells. Am. Soc. Clin. Invest. 100, 2347–2353. Wang, Z.-Y., Olson, E.B., Bjorling, D.E., Mitchell, G.S., Bisgard, G.E., 2008. Sustained hypoxia-induced proliferation of carotid body type I cells in rats. J. Appl. Physiol. 104, 803–808. Ward, S., Bishop, C.M., Woakes, A.J., Butler, P.J., 2002. Heart rate and the rate of oxygen consumption of flying and walking barnacle geese (Branta leucopsis) and bar- headed geese (Anser indicus). J. Exp. Biol. 205, 3347–3356. Weber, R.E., Fago, A., 2004. Functional adaptation and its molecular basis in vertebrate hemoglobins, neuroglobins and cytoglobins. Respir. Physiol. Neurobiol. 144, 141–159. Weisbrod, C.J., Minson, C.T., Joyner, M.J., Halliwill, J.R., 2001. Effects of regional phentolamine on hypoxic vasodilation in healthy humans. J. Physiol. 537, 613–621. West, J.B., 2009. Comparative physiology of the pulmonary blood-gas barrier: the unique avian solution. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1625–R1634. West, J.B., Watson, R.R., Fu, Z., 2007. Major differences in the pulmonary circulation between birds and mammals. Respir. Physiol. Neurobiol. 157, 382–390. Wilkinson, K.A., Huey, K., Dinger, B., He, L., Fidone, S., Powell, F.L., 2010. Chronic hypoxia increases the gain of the hypoxic ventilatory response by a mechanisms in the central nervous system. J. Appl. Physiol. 109, 424–430. Williams, S.E., Wootton, P., Mason, H.S., Bould, J., Iles, D.E., Riccardi, D., Peers, C., Kemp, P.J., 2004. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306, 2093–2097. Yilmaz, C., Hogg, D., Ravikumar, P., Hsia, C.C.W., 2005. Ventilatory acclimatization in awake guinea pigs raised at high altitude. Respir. Physiol. Neurobiol. 145, 235–242. Zhang, L., 2005. Prenatal hypoxia and cardiac programming. J. Soc. Gynecol. Investig. 12, 2–13. Zoer, B., Kessels, L., Vereijken, A., De Mey, J.G.R., Bruggeman, V., Decuypere, E., Blanco, C.E., Villamor, E., 2009. Effects of prenatal hypoxia on pulmonary vascular reactivity in chickens prone to pulmonary hypertension. J. Physiol. Pharmacol. 60 (199-130).


Cortical computation in mammals and birds.

Experimental Divergences in the Visual Cognition of Birds and Mammals.

Seasonal control of gonadotropin-inhibitory hormone (GnIH) in birds and mammals.

Asymmetric and globular forms of acetylcholinesterase in mammals and birds.

Myoglobin oxygen affinity in aquatic and terrestrial birds and mammals.

Sleep and memory in mammals, birds and invertebrates.

Daily torpor and hibernation in birds and mammals.

Occurrence and polymorphism of bombesin-like peptides in the gastrointestinal tract of birds and mammals.

The pathogenicity of swan derived H5N1 virus in birds and mammals and its gene analysis.

Lentiviral vectors containing mouse Csf1r control elements direct macrophage-restricted expression in multiple species of birds and mammals.

The importance of the altricial - precocial spectrum for social complexity in mammals and birds - a review.

Outbreak of type C botulism in birds and mammals in the Emilia Romagna region, northern Italy.

Fetal breathing and development of control of breathing.

Sleep apnea ABCs: airway, breathing, circulation.

Energy requirements for maintenance and growth of wild mammals, birds and reptiles in captivity.

Ultraviolet vision and avoidance of power lines in birds and mammals.

Control of the splanchnic circulation.

Spatial climate patterns explain negligible variation in strength of compensatory density feedbacks in birds and mammals.

Comparison between Timelines of Transcriptional Regulation in Mammals, Birds, and Teleost Fish Somitogenesis.

Scaling of convex hull volume to body mass in modern primates, non-primate mammals and birds.

Serologic evidence of Toxoplasma gondii infection in wild birds and mammals from southeast Brazil.

A comparative study of hypoxanthine phosphoribosyltransferse activity in birds and mammals.

Migratory birds reinforce local circulation of avian influenza viruses.

Deadly hairs, lethal feathers--convergent evolution of poisonous integument in mammals and birds.