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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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Pacemaker cell characteristics of differentiated and HCN4-transduced human mesenchymal stem cells. Life Sci. 2019 Sep 1;232:116620. doi: 10.1016/j.lfs.2019.116620. Epub 2019 Jul 7.

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Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model. Thorac Cardiovasc Surg. 2019 Sep;67(6):503-512. doi: 10.1055/s-0038-1673633. Epub 2018 Oct 23.

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The C-terminal HCN4 variant P883R alters channel properties and acts as genetic modifier of atrial fibrillation and structural heart disease. Biochem Biophys Res Commun. 2019 Aug 31. pii: S0006-291X(19)31679-1. doi: 10.1016/j.bbrc.2019.08.150. [Epub ahead of print]

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The neuronal oxygen-sensing pathway controls postnatal vascularization of the murine brain. FASEB J. 2019 Aug 30:fj201901385RR. doi: 10.1096/fj.201901385RR. [Epub ahead of print]

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Endothelial cell modulation of cardiomyocyte gene expression. Exp Cell Res. 2019 Aug 20:111565. doi: 10.1016/j.yexcr.2019.111565. [Epub ahead of print]

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Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment. Mol Ther. 2019 Aug 7;27(8):1507-1526. doi: 10.1016/j.ymthe.2019.05.008. Epub 2019 May 16.

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Functional association of a CD40 gene single nucleotide polymorphism with the pathogenesis of coronary heart disease. Cardiovasc Res. 2019 Aug 2. pii: cvz206. doi: 10.1093/cvr/cvz206. [Epub ahead of print]

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Plants Neither Possess nor Require Consciousness. Trends Plant Sci. 2019 Aug;24(8):677-687. doi: 10.1016/j.tplants.2019.05.008. Epub 2019 Jul 3.

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Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling. Nat Commun. 2019 Jul 23;10(1):3295. doi: 10.1038/s41467-019-11261-2.

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15-Deoxy-Δ12,14-Prostaglandin J2 Reinforces the Anti-Inflammatory Capacity of Endothelial Cells with a Genetically Determined Nitric Oxide Deficit. Circ Res. 2019 Jul 19;125(3):282-294. doi: 10.1161/CIRCRESAHA.118.313820. Epub 2019 Jun 19.

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Persistent increase in ventral hippocampal long-term potentiation by juvenile stress: A role for astrocytic glutamine synthetase. Glia. 2019 Jul 17. doi: 10.1002/glia.23683. [Epub ahead of print]

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Angioneurins-key regulators of blood-brain barrier integrity during hypoxic and ischemic brain injury. Prog Neurobiol. 2019 Jul;178:101611. doi: 10.1016/j.pneurobio.2019.03.004. Epub 2019 Apr 7. Review.

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Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer. Int J Cancer. 2019 May 28. doi: 10.1002/ijc.32481. [Epub ahead of print]

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TRPC channels are not required for graded persistent activity in entorhinal cortex neurons. Hippocampus. 2019 Apr 19. doi: 10.1002/hipo.23094. [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