Publication : The influence of environmental hypoxia in the physiological responses of laboratory rats and mice during postnatal life and adulthood
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2016
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Il existe chez les différentes espèces de rongeurs une importante variabilité dans les capacités à établir des colonies stables en haute altitude (HA). Par exemple, on trouve des souris (Mus) jusqu'à 4000m alors qu’il n’y a pas de rats (Rattus). La capacité des animaux à survivre et réaliser des activités physiques en HA dépend d’adaptations biologiques physiologiques (plasticité phénotypique) et génétiques ou épigénétiques. Des rats Sprague Dawley (SD) maintenus en HA dans des conditions de laboratoire survivent pendant plusieurs générations (La Paz, Bolivia – 3600m) mais présentent des signes de maladaptations physiologiques (érythrocytose excessive, hypertrophie ventriculaire droite – signe d’hypertension artérielle pulmonaire – et altération des structures alvéolaires avec élargissements des espaces pulmonaires). Ces réponses sont principalement liées à une hypersensibilité au niveau d’oxygène (O2) ambient au cours de la période postnatale et élever les rats de HA à une pression d’O2 reproduisant celle du niveau de la mer (NM) au cours de cette période améliore significativement leur adaptation physiologique1,2. Actuellement, aucune adaptation génétique n’a été mise en évidence chez des souris (Mus musculus) sauvages capturées en HA. Notre hypothèse générale est que les souris possèdent des caractéristiques physiologiques spécifiques qui assurent leur survie en HA. Pour répondre à cette hypothèse, nous avons réalisé 4 études comparant les réponses physiologiques (ventilation, métabolisme, hématologie, saturation artérielle en O2 et rythme cardiaque) entre des souris FVB et des rats SD élevés au NM (Québec, Canada) ou en HA (La Paz, Bolivie – 3600m). Nos principaux résultats démontrent que, par rapport aux rats, les souris adultes de HA présentent une surface alvéolaire augmentée associée avec une meilleure extraction d’O2 sans augmentation excessive de l’érythrocytose ni hypertrophie ventriculaire. Au NM, en conditions ambiantes, les deux espèces présentent des réponses physiologiques similaires. Par contre, après 6h d’exposition en hypoxie (12% d’O2), par rapport aux rats, les souris augmentent leur ventilation minute et diminuent leur métabolisme. Les souris augmentent également l’expression de l’hypoxia inducible factor 1 (HIF-1 – molécule principale de régulation des réponses cellulaires en hypoxie) dans le tronc cérébral après 6h d’hypoxie (15% d’O2) ; cet effet n’est pas présent chez les rats. Au NM, l’hypoxie postnatale induit une augmentation du volume pulmonaire et de la réponse ventilatoire à l’hypoxie chez les souris mais pas chez les rats. Cependant, chez les jeunes rats de HA, l’architecture pulmonaire est préservée comparée aux rats exposés en hypoxie postnatale au NM. En conclusion, les rats vivant en HA depuis plusieurs générations présentent des stratégies physiologiques pour faire face au manque d’O2 ambient leur permettant de survivre dans des conditions de laboratoire mais qui ne sont pas suffisantes pour assurer leur survie en milieu sauvage. Nos résultats confirment également que les souris possèdent des prédispositions physiologiques permettant la survie en altitude.
Different rodent species present divergent abilities to colonize and establish stable colonies at high altitude (HA). Ecological studies show that mice (Mus) can be found at HA (up to 4000m) while rats (Rattus) are absent. The ability of an animal to survive and do physical activities at HA depends upon biological adaptations that can include physiological (phenotypical plasticity) and genetic, or epigenetic modifications. Adult Sprague Dawley (SD) rats can live under laboratory conditions at HA for several generations (La Paz, Bolivia – 3600m), but they display signs of physiological maladaptation such as excessive erythrocytosis, right ventricular hypertrophy (a sign of pulmonary hypertension) and altered alveolar structure with enlarged airspace in the lungs. These responses are mainly linked to an excessive sensibility to the oxygen (O2) ambient level during postnatal life. Indeed, raising the HA rats under sea level (SL) O2 pressure during early postnatal life significantly improved the physiological adaptation1,2. Furthermore, in HA wild mice (Mus musculus) living at HA, there is no signs of genetic adaptation to this environment. Accordingly, our general hypothesis is that mice possess specific physiological traits ensuring survival at HA. To assess this hypothesis, we conducted 4 studies to compare physiological responses (including ventilation, metabolic rate, hematology, lung morphology, arterial O2 saturation and heart rate) between FVB mice and SD rats raised at SL (Quebec, Canada) or HA (La Paz, Bolivia – 3600m). Our main results show that compared with rats, HA adult mice display enhanced alveolar surface area associated with increased O2 extraction, and avoid excessive erythrocytosis and right ventricular hypertrophy. At SL, under ambient conditions, mice and rats display similar physiological variables. However, after 6 hours of sustained hypoxia (12% O2), mice have higher minute ventilation and lower metabolic rate than rats. Mice also had an increased expression of the hypoxia inducible factor 1 (HIF-1 – the principal mediator of the cellular responses in hypoxia) in the brainstem after 6 hours of hypoxia (15% O2), while this response was not observed in rats. Hypoxic exposure during postnatal life at SL increased the lung volume and the hypoxic ventilatory response in mice but not rats. However, young HA rats preserve their lung architecture compared with young SL rats exposed to postnatal hypoxia. We conclude that rats living at HA for several generations display physiological strategies to cope with the ambient hypoxia that allow them to survive in laboratory conditions but are not sufficient to establish stables colonies in the wild. Also, our results confirm that mice are predisposed to withstand hypoxic environment.
Different rodent species present divergent abilities to colonize and establish stable colonies at high altitude (HA). Ecological studies show that mice (Mus) can be found at HA (up to 4000m) while rats (Rattus) are absent. The ability of an animal to survive and do physical activities at HA depends upon biological adaptations that can include physiological (phenotypical plasticity) and genetic, or epigenetic modifications. Adult Sprague Dawley (SD) rats can live under laboratory conditions at HA for several generations (La Paz, Bolivia – 3600m), but they display signs of physiological maladaptation such as excessive erythrocytosis, right ventricular hypertrophy (a sign of pulmonary hypertension) and altered alveolar structure with enlarged airspace in the lungs. These responses are mainly linked to an excessive sensibility to the oxygen (O2) ambient level during postnatal life. Indeed, raising the HA rats under sea level (SL) O2 pressure during early postnatal life significantly improved the physiological adaptation1,2. Furthermore, in HA wild mice (Mus musculus) living at HA, there is no signs of genetic adaptation to this environment. Accordingly, our general hypothesis is that mice possess specific physiological traits ensuring survival at HA. To assess this hypothesis, we conducted 4 studies to compare physiological responses (including ventilation, metabolic rate, hematology, lung morphology, arterial O2 saturation and heart rate) between FVB mice and SD rats raised at SL (Quebec, Canada) or HA (La Paz, Bolivia – 3600m). Our main results show that compared with rats, HA adult mice display enhanced alveolar surface area associated with increased O2 extraction, and avoid excessive erythrocytosis and right ventricular hypertrophy. At SL, under ambient conditions, mice and rats display similar physiological variables. However, after 6 hours of sustained hypoxia (12% O2), mice have higher minute ventilation and lower metabolic rate than rats. Mice also had an increased expression of the hypoxia inducible factor 1 (HIF-1 – the principal mediator of the cellular responses in hypoxia) in the brainstem after 6 hours of hypoxia (15% O2), while this response was not observed in rats. Hypoxic exposure during postnatal life at SL increased the lung volume and the hypoxic ventilatory response in mice but not rats. However, young HA rats preserve their lung architecture compared with young SL rats exposed to postnatal hypoxia. We conclude that rats living at HA for several generations display physiological strategies to cope with the ambient hypoxia that allow them to survive in laboratory conditions but are not sufficient to establish stables colonies in the wild. Also, our results confirm that mice are predisposed to withstand hypoxic environment.
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