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Joint Meeting of the Federation of European Physiological Societies and the Austrian Physiological Society

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09/13/2017 - Hall B | 3:00pm - 5:00pm 
Symposium 4: Current developments in the pulmonary circulation

Organizers: A. Olschewski (Graz, Austria); G. Kwapiszewska (Graz, Austria)

3:00pm
S04-1
Sphingolipids - new players in pulmonary vasoconstriction and lung vascular remodeling
*Wolfgang  Kübler1
1 Charité-Universitätsmedizin Berlin, Institute of Physiology, Berlin, Germany
Abstract text :

Sphingolipids are a class of lipids that contain a backbone of sphingoid bases. Of late, sphingolipids, and specifically ceramide and sphingosine-1-phosphate (S1P) have emerged as important mediators of cell and organ homeostasis as well as key signaling molecules involved in the pathogenesis of cardiovascular and respiratory diseases. There is so far no known receptor for ceramide; however, ceramide activates a series of downstream signalling pathways by formation of ceramide-rich lipid rafts and caveolae which cluster receptor molecules and recruit intracellular signalling molecules. S1P acts as intracellular signalling molecule by mechanisms that are likely similar to those of ceramide. On the other hand, S1P signals as extracellular mediator via five cell surface G-protein coupled receptors (GPCRs) termed S1P1-5.


Both S1P and ceramide have recently become implicated in the regulation of lung vascular tone and remodeling. Neutral sphingomyelinase, which generates ceramide from sphingomyelin at the outer leaflet of the cell membrane, mediates hypoxic pulmonary vasoconstriction (HPV) by promoting the recruitment of transient receptor potential canonical 6 (TRPC6) Ca2 channels that are essential for HPV to caveolae in a process that surprisingly is dependent on cystic fibrosis transmembrane conductance regulator (CFTR). Via activation of S1P2 receptors, S1P concurrently activates both Rho kinase signaling and - via phospholipase C - TRPC6 which conjointly cause smooth muscle cell contraction. In chronic hypoxia, prolonged stimulation of S1P2 promotes lung vascular remodeling by stimulating both smooth muscle cell proliferation as well as hypertrophy. As such, sphingolipids may present promising targets for the prevention or reversal of lung vascular remodeling and pulmonary hypertension.


 



3:30pm
S04-2
FoxO transcription factors in pulmonary hypertension:Pathophysiology and therapeutic implications
*Soni Savai  Pullamsetti1,2
1 Max-Planck-Institute for Heart and Lung Research, , Bad Nauheim, Germany
2 Justus-Liebig University, Department of Internal Medicine, Giessen, Germany
Abstract text :

Pulmonary hypertension (PH) is a progressive disease of multifactorial etiology, which has a poor prognosis. Variants of PH affect up to 100 million people worldwide. Increased proliferation and migration and resistance to apoptosis of pulmonary vascular cells play a major role in pathologic remodeling processes underlying different variants of PH. Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation, migration, differentiation and apoptosis by modulating and integrating multiple signaling pathways. We have recently observed that in pulmonary vessels and pulmonary vascular smooth muscle cells and adventitial fibroblasts of patients with different groups of PH (group 1: Pulmonary arterial hypertension; group 3: PH associated with lung diseases) and lungs with experimental PH, FoxO isoforms (FoxO1, FoxO3) are inactivated via phosphorylation and nuclear exclusion. In addition, we have identified the receptor tyrosine kinase (via PI3K/AKT), cytokine (via STAT3) and Hippo signaling as upstream pathways mediating FoxO´s control of PH. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells and FoxO3 in fibroblasts reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO activity using paclitaxel/ UCN-01, or reconstitution of the transcriptional activity of FoxO1 or FoxO3 by gene therapy, restored the physiologically quiescent vascular phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Taken together our studies have provided strong evidence for the involvement of FoxO proteins in PH pathogenesis and FoxO-reactivation offers a potential therapeutic option for PH.



4:00pm
S04-3
Adapting to high altitude
*Max  Gassmann1
1 University of Zurich, , Zurich, Switzerland
Abstract text :

Highlanders are well adapted to live at high altitude, and so is the developing human fetus. In a prospective observational study on healthy term newborns in Peru (Puno at 3840m) that included novel non-invasive visualization of microcirculation we demonstrated that vessel density is elevated by 14% in neonates born to women living at high altitude as compared to babies born at sea level, most likely revealing an early adaptive mechanism to a highly hypoxic antenatal environment.


As regarding ascending mountaineers, adequate acclimatization time to slowly adjust to hypoxic conditions is one of the most important aspects. Thus, it is crucial to focus on the crosstalk between oxygen and iron homeostasis. To ensure that sufficient iron is provided for red blood cell production, hypoxia-induced soluble factors - such as the novel Epo-controlled erythroferrone that is expressed in erythroid precursor cells - reach the liver where they reduce expression of the iron hormone hepcidin. In turn, suppression of hepcidin allows both, elevated iron release from storage organs and enhanced absorption of dietary iron by enterocytes.


Living at moderate to high altitude leads to the elevation of hemoglobin (Hb) levels in humans but scarce information exists on the effect of lower altitude on erythrocyte production. We compared several parameters including Hb values to the residence altitude of about 70"000 Swiss men aged 18-22 years. We observed a significant increase of Hb values for every 300 meters of augmented altitude the young Swiss men live at. Thus, even a modest increase in the residence altitude significantly elevates Hb values. Apart from gender, age, ethnicity and socio-economical effects, altitude should be considered when defining the Hb threshold for a given population even when residing at altitudes below 1000 m above sea level.


 



4:30pm
S04-4 (O)
Alveolar oxygen respiratory oscillations measured in arterial blood.
*Federico Formenti1,2, Nikhil Bommakanti2, Rongsheng Chen2, John Cronin1, Hanne McPeak2, Delphine Holopherne-Doran3, Göran Hedenstierna4, Clive Hahn2, Anders Larsson4, Andrew Farmery2
1 King's College London, , London, United Kingdom
2 University of Oxford, , Oxford, United Kingdom
3 University of Bristol, , Bristol, United Kingdom
4 University of Uppsala, , Uppsala, Sweden
Abstract text :

The partial pressure of oxygen in arterial blood can increase during inspiration and decrease during expiration in the presence of a variable shunt fraction, such as with cyclical atelectasis, but it is generally presumed to remain constant within a respiratory cycle in the healthy lung. In our experiments, arterial oxygen partial pressure was measured continuously with a fast intravascular sensor in the carotid artery of anaesthetized, mechanically ventilated pigs, without lung injury. Here we demonstrate that the partial pressure of arterial oxygen shows respiratory oscillations in the uninjured pig lung, in the absence of cyclical atelectasis (determined with dynamic computed tomography), with oscillation amplitudes that exceeded 50 mmHg, depending on the mechanical ventilation conditions. These respiratory oscillations in the partial pressure of arterial oxygen can be modelled from a single alveolar compartment and a constant oxygen uptake, without the requirement for an increased shunt fraction during expiration. Our results are likely to contribute to the interpretation of arterial oxygen respiratory oscillations observed during mechanical ventilation in animal models of the acute respiratory distress syndrome.



4:45pm
S04-5 (O)
Brain-derived neurotrophic factor mRNA expression in peripheral and cerebral vessels : Impact of physical training
*Marina Cefis1, Aurore Quirié1, Christine Marie1, Anne Prigent-Tessier1, Philippe Garnier1
1 Université de Bourgogne Franche-comté , , DIJON, France
Abstract text :

Questions:


For a long time, the neuron was considered as the preponderant cellular source of cerebral brain-derived neurotrophic factor (BDNF). However, we recently showed that the cardiovascular system contains as much BDNF as the brain with a prominent expression in endothelial cells and that physical training (PT) increases BDNF protein levels in both peripheral (aorta) and cerebral vessels. In this context, the aim of the present study was to determine i) if these vessels expressed BDNF mRNA and ii) the impact of PT on BDNF gene expression.


Methods:


Experiments were performed on 2 groups of WISTAR male rats: sedentary and exercised. Exercise was induced by a treadmill run (18 m/min, 30 min/day) for 7 consecutive days. BDNF, eNOS (as a marker of shear stress) and Tie2 (a specific marker of endothelial cells) mRNA expressions were measured by RT-qPCR in peripheral (abdominal aorta) and cerebral microvessels.


Results:


BDNF mRNA was expressed in both peripheral and cerebral vessels correlated with endothelial cells enrichment (Tie-2). However, while PT significantly increased eNOS and BDNF mRNA levels in cerebral microvessels, it was without effect in aorta.


Conclusions:                                                      


The present study is the first to show that both peripheral and cerebral vessels expressed BDNF gene. The differential expression between peripheral and cerebral vessels in response to PT could be explained either by differences in endothelial cells enrichment and/or in shear stress at the surface of the endothelium (inversely proportional to the diameter), which are both higher in cerebral microvessels than in aorta.