Erythropoietin modulates the neural control of hypoxic ventilation

Numerous factors involved in general homeostasis are able to modulate ventilation. Classically, this comprises several kind of molecules, including neurotransmitters and steroids that are necessary for fine tuning ventilation under different conditions such as sleep, exercise, and acclimatization to high altitude. Recently, however, we have found that erythropoietin (Epo), the main regulator of red blood cell production, influences both central (brainstem) and peripheral (carotid bodies) respiratory centers when the organism is exposed to hypoxic conditions. Here, we summarize the effect of Epo on the respiratory control in mammals and highlight the potential implication of Epo in the ventilatory acclimatization to high altitude, as well as in the several respiratory sickness and syndromes occurring at low and high altitude. (Part of a multi-author review.

Regular endurance training reduces the exercise induced HIF-1α and HIF-2α mRNA expression in human skeletal muscle in normoxic conditions

Regular exercise induces a variety of adaptive responses that enhance the oxidative and metabolic capacity of human skeletal muscle. Although the physiological adjustments of regular exercise have been known for decades, the underlying mechanisms are still unclear. The hypoxia inducible factors 1 and 2 (HIFs) are clearly related heterodimeric transcription factors that consist of an oxygen-depended α-subunit and a constitutive β-subunit. With hypoxic exposure, HIF-1α and HIF-2α protein are stabilized. Upon heterodimerization, HIFs induce the transcription of a variety of genes including erythropoietin (EPO), transferrin and its receptor, as well as vascular endothelial growth factor (VEGF) and its receptor. Considering that several of these genes are also induced with exercise, we tested the hypothesis that the mRNA level of HIF-1α and HIF-2α subunits increases with a single exercise bout, and that this response is blunted with training. We obtained muscle biopsies from a trained (5days/week during 4weeks) and untrained leg from the same human subject before, immediately after, and during the recovery from a 3h two-legged knee extensor exercise bout, where the two legs exercised at the same absolute workload. In the untrained leg, the exercise bout induced an increase (P<0.05) in HIF-1α fold and HIF-2α fold mRNA at 6h of recovery. In contrast, HIF-1α and HIF-2α mRNA levels were not altered at any time point in the trained leg. Obviously, HIF-1α and HIF-2α mRNA levels are transiently increased in untrained human skeletal muscle in response to an acute exercise bout, but this response is blunted after exercise training. We propose that HIFs expression is upregulated with exercise and that it may be an important transcription factor that regulates adaptive gene responses to exercis

Regulating cellular oxygen sensing by hydroxylation

Oxygen homeostasis under conditions of limited O2 supply requires hypoxia-dependent gene regulation. The transcription factor complex hypoxia-inducible factor 1 (HIF-1) has been recognized as the master regulator that mediates the adaptational genetic response to ensure restoration of energy supply. This review will focus on the recent advances in understanding the hypoxia-induced cellular response with particular respect to cellular O2 sensing for adequate control of HIF-1 activatio

The geographical ancestry affects normal hemoglobin values in high-altitude residents

Increasing the hemoglobin (Hb) concentration is a major mechanism adjusting arterial oxygen content to decreased oxygen partial pressure of inspired air at high altitude. Approximately 5% of the world's population living at altitudes higher than 1500 m shows this adaptive mechanism. Notably, there is a wide variation in the extent of increase in Hb concentration among different populations. This short review summarizes available information on Hb concentrations of high-altitude residents living at comparable altitudes (3500-4500 m) in different regions of the world. An increased Hb concentration is found in all high-altitude populations. The highest mean Hb concentration was found in adult male Andean residents and in Han-Chinese living at high altitude, whereas it was lowest in Ethiopians, Tibetans, and Sherpas. A lower plasma volume in Andean high altitude natives may offer a partial explanation. Indeed, male Andean high-altitude natives have a lower plasma volume than Tibetans and Ethiopians. Moreover, Hb values were lower in adult, non-pregnant females than in males; differences between populations of different ancestry were less pronounced. Various genetic polymorphisms were detected in high altitude residents thought to favor life in a hypoxic environment, some of which correlate with the relatively low Hb concentration in the Tibetans and Ethiopians, whereas differences in angiotensin-converting enzyme allele-distribution may be related to elevated Hb in the Andeans. Taken together these results indicate different sensitivity of oxygen dependent control of erythropoiesis or plasma volume among populations of different geographical ancestry, offering explanations for differences in the Hb concentration at high altitude

Erythropoietin but not VEGF has a protective effect on auditory hair cells in the inner ear

It has recently been shown that the oxygen-regulated factors erythropoietin (Epo) and vascular endothelial growth factor (VEGF) confer protection on different cells, including neuronal-derived ones. The receptors for Epo and VEGF are widely expressed in different organs. Since mammalian auditory hair cells can irreversibly be damaged by different agents, we aimed to identify otoprotective compounds. We focused on the role of Epo and VEGF in the inner ear and review the recent studies. Epo and its receptor are expressed in the inner ear. In vitro experiments on auditory hair cells showed a protective effect of Epo in ischemia- and gentamicin-induced hair cell damage. In contrast, an in vivo study using an animal model of noise-induced hearing loss showed a negative effect of Epo. Also VEGF and its receptors are expressed in the inner ear. Changes in the expression of VEGF or its receptors have been found in the cochlea after noise exposure, transcranial vibration and diabetic or aged animals. Until now, there are no studies about a direct effect of VEGF on auditory hair cells in vitro or in vivo. We could exclude a protective effect of VEGF on gentamicin-induced auditory hair cell damage in vitro. Thus, we conclude that Epo but not VEGF has a protective effect on auditory hair cell damage at least in vitro. (Part of a multi-author review.

Optimized surgical techniques and postoperative care improve survival rates and permit accurate telemetric recording in exercising mice

BACKGROUND: The laboratory mouse is commonly used as a sophisticated model in biomedical research. However, experiments requiring major surgery frequently lead to serious postoperative complications and death, particularly if genetically modified mice with anatomical and physiological abnormalities undergo extensive interventions such as transmitter implantation. Telemetric transmitters are used to study cardiovascular physiology and diseases. Telemetry yields reliable and accurate measurement of blood pressure in the free-roaming, unanaesthetized and unstressed mouse, but data recording is hampered substantially if measurements are made in an exercising mouse. Thus, we aimed to optimize transmitter implantation to improve telemetric signal recording in exercising mice as well as to establish a postoperative care regimen that promotes convalescence and survival of mice after major surgery in general. RESULTS: We report an optimized telemetric transmitter implantation technique (fixation of the transmitter body on the back of the mouse with stainless steel wires) for subsequent measurement of arterial blood pressure during maximal exercise on a treadmill. This technique was used on normal (wildtype) mice and on transgenic mice with anatomical and physiological abnormalities due to constitutive overexpression of recombinant human erythropoietin. To promote convalescence of the animals after surgery, we established a regimen for postoperative intensive care: pain treatment (flunixine 5 mg/kg bodyweight, subcutaneously, twice per day) and fluid therapy (600 mul, subcutaneously, twice per day) were administrated for 7 days. In addition, warmth and free access to high energy liquid in a drinking bottle were provided for 14 days following transmitter implantation. This regimen led to a substantial decrease in overall morbidity and mortality. The refined postoperative care and surgical technique were particularly successful in genetically modified mice with severely compromised physiological capacities. CONCLUSION: Recovery and survival rates of mice after major surgery were significantly improved by careful management of postoperative intensive care regimens including key supportive measures such as pain relief, administration of fluids, and warmth. Furthermore, fixation of the blood pressure transmitter provided constant reliable telemetric recordings in exercising mice

P-274: Activated endothelin system in polyglobulia

The role of the endothelin system, the functional counterpart of NO, in the pathophysiology of polyglobulia remains still elusive. Therefore a novel erythropoietin overexpressing mouse was generated, with hematocrit levels of about 80%. Hence, we analyzed vascular contractions to ET-1 and big endothelin-1 (big ET-1), endothelin-1 (ET-1) promoter activity, ET-1 immunochemistry, endothelin-1 (ET-1)-protein tissue levels, ETA/B-receptor mRNA expression in this novel transgenic model of severe polyglobulia. For analysis of ET-1 promotor activity, EPO transgenic mice were mated with homozygous transgenic mice expressing the lacZ gene under control of the human ET-1 promoter and immunochistochemistry for gal blue was performed in lacZ transgenic animals. Notwithstanding markedly increased eNOS expression, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels indicating enhanced bioavailability of NO, ET-1 tissue levels were also augmented in heart, kidney, liver and aorta (2.2±0.3 vs. 0.5±0.1 pg/mg tissue; P<0.01) of transgenic polyglobulic animals. Accordingly, immunohistochemistry demonstrated enhanced expression of ET-1 protein in the vascular wall of polyglobulic animals as compared to controls (p< 0.05), while increase of ET-1 promoter activity was confined to the perivascular tissue (P<0.05). NOS inhibition with L-NAME unmasked increased vascular reactivity to ET-1 and bigET-1 and aortic ETA/B receptor mRNA gene expression was enhanced (p<0.05 vs. controls). Administration of the NOS inhibitor L-NAME led to acute vasoconstriction of peripheral resistance vessels, hypertension and death of transgenic mice within 2 days, while wildtypes did not show increased mortality. Treatment with the ETA antagonist darusentan doubled survival time of transgenic polyglobulic mice after NO synthase inhibition (p<0.01 vs placebo). In conclusion, in this study we provide first evidence that the tissue endothelin system is activated by polyglobulia. Together with a stimulated NO system it contributes to cardiovascular regulation in pathophysiological conditions associated with increased hematocri

The Brain at High Altitude: From Molecular Signaling to Cognitive Performance

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity