Cellular and functional response to hypoxia

For the past 20 years our laboratory has been involved in the research on physiological and pathophysiological aspects of adaptation to hypoxia, using animal models (rats, mice, Pika) and clinical studies, leading to a total of 100 publications in peer-reviewed journals for the past 10 years. We have a complete infrastructure for providing a hypoxic environment for rodents in acute and chronic conditions with physiologiocal measurements (plethysmography, catheterism, exercise platform, Biopack). Our laboratory is also equipped with standard cell and molecular biology equipment (Western Blot, RT-PCR, immunohistochemistry, etc.). We developed several clinical trials in patients suffering from acute or chronic diseases linked to exposure to hypoxia (pulmonary hypertension, altitude-induced polycythemia).

Altitude hypoxia and red cells

  •  Human studies

Permanent living at high altitude may provoke diseases characterized by an excessive number of red cells (Chronic Mountain Sickness or Monge’s disease) and/or pulmonary hypertension (High Altitude Pulmonary Hypertension – HAPH). The evolution of these diseases is always very dramatic, towards cardiac failure and cerebral vascular stroke. The prevalence is 10% on the Andean Altiplano (Peru, Bolivia) so that it is an important public health problem in those regions.

Very little information is available on the precise physiopathological mechanisms of these diseases and a genetic predisposition is suspected. We expect to develop collaborative research within GR-Ex to evidence genetic risk factors of this disease thanks to a genetic survey of Monge’s disease that has already started in Peru.

Preliminary results obtained in sea-level natives who suffer from defective acclimatization to acute high altitude exposure let us think that the succino-dehydrogenase (SDHB), enzyme involved in the transport of oxygen in the mitochondria of the chemoreceptors, may play a role in the genetic susceptibility of Monge’s disease or high altitude excessive polycythemia. Moreover, a relation was found between intolerance to acute hypoxia in sea-level natives (acute mountain sickness) and some polymorphism of SDHB. These results shed a new light on the possible link between impairments of oxygen sensing at mitochondrial level and intolerance to high altitude. Hypoxia-induced pulmonary hypertension might also be linked to genetic variants in the systems involved in control of vascular tone and/or remodeling at the pulmonary circulation (VEGF).

Acute exacerbations due to hypoxia can be observed in other diseases such as sickle-cell anemia. In a recent collaboration we started with P. Connes (UMR_S 665), we found a tight link between hemorrheological alterations and cerebral oxygenation as well as between sympathovagal balance and respiratory exacerbations. Our objective is to develop this line of investigation in order to better understand the underlying mechanisms of these alterations and the specific role of hypoxia.

  • Animal models

We developed various animal models helping to unravel these pathophysiological processes. Rats exposed to chronic hypoxia develop an excessive polycythemia due to hypoxia-induced overexpression of erythropoietin (Epo); in parallel, they develop pulmonary hypertension due to both hypoxic pulmonary vasocontriction and increase in blood viscosity. The respective importance of these two factors remains to be established. Mice underexpressing Epo (EpoTagh transgenic mice) are bred in our laboratory and are used to explore the role of Epo in acclimatization to hypoxia. We evidenced a role of Epo in the respiratory control in hypoxia by the medulla. Epo receptors have also been found in various tissues such as skeletal muscle, heart and brain. We also have the opportunity to study the Plateau Pika (a lagomorph adapted to life on the Tibetan plateau at 4000-5000m altitude). We plan to explore several pathways involved in the control of ventilation in those animals, using pharmacological tools (blockade of NOS, NMDA or non-NMDA receptors as well as antagonists of serotonin transporters).

Our model of chronic hypoxiac rats will be used to better understand the interaction between hypoxia, pulmonary hemodynamics and the rheological changes induced by altitude-induced polycythemia. Acetazolamide and other drugs acting directly or indirectly on erythropoiesis will be given to these animals in order to differentiate the intrinsic vascular mechanisms (vasodilation pathways, NO production, etc.) and the changes in blood viscosity by manipulating hematocrit via hemodilution techniques in collaboration with other experts of « GR-Ex » in blood rheology and interactions of red cells with vascular endothelium.

The Epo-TAgh mouse underexpresses Epo, leading to severe anemia. This model wil be used to explore the involvement of Epo-EpoR pathway in the adaptation processes to acute and chronic hypoxia. These mice are able to adapt to severe hypoxic conditions in spite of reduced blood O2 content. Cerebral angiogenesis and increased ventilatory drive are probably key mechanisms to explain this adaptation process. The role of NMDA and Epo receptors, as well as the NO pathway will be explored, with respect to control of ventilation and cerebral blood flow.