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Institute of Physiology and Pathophysiology

Research Areas

Hypoxia in the Brain

Our research group investigates the effects of hypoxia in the brain. Tissue hypoxia in the brain is a central problem in a number of disorders such as ischemia, tumors, brain injury, high altitude sickness and epilepsy. The insufficient availability of oxygen to the cells can be caused by reduced supply or increased consumption. Therefore our interest is focused on the neurovascular interplay which also includes glial cells. We study two hypoxia-related processes in particular: 1) the activation of endogenous factors which protect neurons against cell death or which induce their regeneration (neuroprotection and neurogenesis), and 2) the opening of the blood-brain barrier leading to cerebral oedema formation. We utilise various in vivo experimental models (hypoxia chamber, ischemia models), including transgenic animals, and combine these with modern molecular biology techniques. By analysing and characterising this endogenous protective response we hope to find clues for new therapies for human diseases.

1) Neuroprotection and Neurogenesis


Tissue hypoxia is detected via various oxygen sensors (polylhydoxylases, PHD), which activate specific transcription factors (hypoxia-inducible factors, HIF), which, in turn, lead to the induction of neurogenic and neuroprotective factors such as vascular endothelial growth factor (VEGF) or erythropoietin (Epo). It is the aim of our research to understand in detail the underlying mechanisms and to manipulate them in a positive way.




Brain-specific overexpression of VEGF reduces infarct (pale area) size. Infarct size quantification on cresyl violet-stained brain tissue sections revealed a significant 40% reduction in VEGF transgenic mice (VEGF-tg) as compared with non transgenic littermate controls (ntg).

 

from Wang et al.; Brain (2005); 128: 52-63

2) Blood-Brain Barrier


Besides its positive properties (neuroprotection, neurogenesis, angiogenesis) VEGF has one negative effect on the blood-brain barrier (BBB), which complicates its immediate therapeutic use:  VEGF leads to the opening of the BBB and, as a consequence, to the formation of a cerebral oedema. We investigate the molecular mechanisms of this opening by characterising the processes at the endothelial cell-cell contacts (tight junctions) and at the extracellular matrix. It is our goal to reduce oedema formation by intervention without affecting the neuroprotective properties.

 


Hypoxia causes rearrangement and gap formation of the tight junction protein occludin. Mice were exposed for 48 h to 20% (control) or 8% oxygen (hypoxia). Coronal brain sections were
stained immunohistochemically for occludin (green) and CD31 (red), and nuclei were stained with DAPI (blue). Three-dimensional reconstruction after confocal microscopy demonstrates occludin rearrangement and gap formation (arrowheads) after hypoxia, as compared to the continuous, sharp linear staining (arrows) in controls.

 

from Bauer et al.; J Cereb Blood Flow Metab (2010); 30: 837-848.





Recent Publications

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Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice. FASEB J. 2018 Nov 1:fj201801594R. doi: 10.1096/fj.201801594R. [Epub ahead of print]

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Synaptic entrainment of ectopic action potential generation in hippocampal pyramidal neurons.  J Physiol. 2018 Nov;596(21):5237-5249. doi: 10.1113/JP276720. Epub 2018 Sep 19.

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The Long Noncoding RNA Cancer Susceptibility 9 and RNA Binding Protein Heterogeneous Nuclear Ribonucleoprotein L Form a Complex and Coregulate Genes Linked to AKT Signaling. Hepatology. 2018 Nov;68(5):1817-1832. doi: 10.1002/hep.30102. Epub 2018 Oct 12.

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Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model. Thorac Cardiovasc Surg. 2018 Oct 23. doi: 10.1055/s-0038-1673633. [Epub ahead of print]

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Early appearance and spread of fast ripples in the hippocampus in a model of cortical traumatic brain injury. J Neurosci. 2018 Oct 17;38(42):9034-9046. doi: 10.1523/JNEUROSCI.3507-17.2018. Epub 2018 Sep 6.

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High-fat diet suppresses the positive effect of creatine supplementation on skeletal muscle function by reducing protein expression of IGF-PI3K-AKT-mTOR pathway. PLoS One. 2018 Oct 4;13(10):e0199728. doi: 10.1371/journal.pone.0199728. eCollection 2018.

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Alcohol reduces muscle fatigue through atomistic interactions with nicotinic receptors. Commun Biol. 2018 Oct 3;1:159. doi: 10.1038/s42003-018-0157-9. eCollection 2018.

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Possible neurotoxicity of the anesthetic propofol: evidence for the inhibition of complex II of the respiratory chain in area CA3 of rat hippocampal slices. Arch Toxicol. 2018 Oct;92(10):3191-3205. doi: 10.1007/s00204-018-2295-8. Epub 2018 Aug 24.

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Endothelial progenitor cells accelerate endothelial regeneration in an in vitro model of Shigatoxin-2a-induced injury via soluble growth factors. Am J Physiol Renal Physiol. 2018 Oct 1;315(4):F861-F869. doi: 10.1152/ajprenal.00633.2017. Epub 2018 Mar 7.

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Strategy for marker-based differentiation of pro- and anti-inflammatory macrophages using matrix-assisted laser desorption/ionization mass spectrometry imaging. Analyst. 2018 Sep 10;143(18):4273-4282. doi: 10.1039/c8an00659h. Epub 2018 Jul 20.

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Recent advances in hippocampal structure and function. Cell Tissue Res. 2018 Sep;373(3):521-523. doi: 10.1007/s00441-018-2913-z. Epub 2018 Aug 20. doi: 10.1007/s00441-018-2913-z. Editorial. No abstract available.

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Electrical coupling between hippocampal neurons: contrasting roles of principal cell gap junctions and interneuron gap junctions. Cell Tissue Res. 2018 Sep;373(3):671-691. doi: 10.1007/s00441-018-2881-3. Epub 2018 Aug 15. Review.

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Metabolic modulation of neuronal gamma-band oscillations. Pflugers Arch2018 Sep;470(9):1377-1389. doi: 10.1007/s00424-018-2156-6. Epub 2018 May 28.

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NFAT5 Isoform C Controls Biomechanical Stress Responses of Vascular Smooth Muscle Cells. Front Physiol. 2018 Aug 23;9:1190. doi: 10.3389/fphys.2018.01190. eCollection 2018.

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Selective vulnerability of αOFF retinal ganglion cells during onset of autoimmune optic neuritis. Neuroscience. 2018 Jul 31. pii: S0306-4522(18)30515-3. doi: 10.1016/j.neuroscience.2018.07.040. [Epub ahead of print]

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The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function. FASEB J. 2018 Jun 7:fj201800246R. doi: 10.1096/fj.201800246R. [Epub ahead of print]


Institute of
Physiology and Pathophysiology

Heidelberg University

Im Neuenheimer Feld 326

69120 Heidelberg

Germany

Phone:+49 6221 54-4035
Fax:+49 6221 54-4038
E-mail:sekretariat.hecker@
physiologie.uni-heidelberg.de