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Institute of Physiology and Pathophysiology

Korff Group

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Biomechanically Triggered Remodeling in the Cardiovascular System

 

Cardiovascular research belongs to the most rapidly growing biomedical disciplines as it deals predominantly with diseases that are the leading cause of death in industrial countries. These include, but are not limited to coronary heart disease, cardiomyopathy, hypertension and arterial disease, heart hypertrophy, heart failure, arteriosclerosis, stroke, peripheral arterial disease and varicosis.

   

The focus of my group is on the investigation of biomechanically triggered mechanisms which either promote cardiovascular diseases or at least partially compensate their harmful effects. Therefore, we are especially interested in the analysis of cardiac insufficiency, development of arteriosclerotic lesions, hypertension-induced arterial remodeling, varicose vein formation as well as arteriogenesis, the formation of collateral arteries from preexisting arterioles to compensate the occlusion of a conduit artery.

 

All of these pathophysiological processes are basically associated with the adaptive or maladaptive remodeling of the cardiac or vessel wall, which is strictly dependent on phenotypic changes of the corresponding tissue-specific cells, namely cardiomyocytes, endothelial and vascular smooth muscle cells. Against this background, our working hypothesis is that biomechanical deformation of cells in cardiovascular tissues is an important determinant of their phenotype and sufficient to initiate pathophysiological remodeling processes.

  

   

     

Biomechanical deformation (stretch) of smooth muscle cells is determined by circumferential wall stress (St )

Wall stress is defined by the law of Laplace. Its chronic increase (e.g. by a hypertension-induced increase in the transmural pressure difference) induces the deformation (stretch) of endothelial cells (EC) and vascular smooth muscle cells (SMC) in the blood vessel wall, which may elicit pathophysiological remodeling processes of the cardiac or vessel wall.

   

   

In fact, hypertension-induced arterial remodeling, arteriogenesis, (afterload-related) cardiac insufficiency, endothelial dysfunction at arteriosclerotic predilection sites, as well as varicose vein formation are all associated with or elicited by a chronic increase in wall stress.

  

 

 

Our previous work encompasses several topics of cardiovascular research and has underlined the relevance of this biomechanical force for changes in the phenotype of endothelial and vascular smooth muscle cells.

   

   

Stretch is an important trigger of vascular remodeling processes.

 


  

Korff et al., Circulation 2007
Korff et al., Blood 2008
Demicheva et al., Circ. Res. 2008



Hypertension impairs expression of “contractile gene products” in vascular SMCs.

 


  

Pfisterer et al., Cardiovasc. Res., 2012



Wall stress is sufficient to trigger varicose vein development.

 


  

Feldner et al., FASEB J, 2011

 

 

To achieve a better understanding of the intracellular signaling mechanisms that are triggered by an increase in wall stress, our experimental portfolio includes multiple in vitro and in vivo techniques: In vitro we utilize the FlexCell system, which allows us to expose cultured cells to defined levels of cyclic stretch. This system is used for basic mechanistic studies which help us to identify new stretch-regulated target molecules. In addition, we perfuse isolated mouse arteries and veins under defined pressure/flow conditions in order to closely mimic the in vivo environment.

 
In vivo, we employ various hypertension models and the hindlimb ischemia model in which the occlusion of the femoral artery induces arteriogenic remodeling of the collateral arterioles. We also take advantage of our specialized mouse auricle artery/vein ligation models, which allow for the easy visualization and measurement of changes in the vascular architecture and the local transdermal application of experimental reagents (e.g. decoy oligodeoxynucleotides).

  


Recent Publications

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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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Electrical coupling between hippocampal neurons: contrasting roles of principal cell gap junctions and interneuron gap junctions. Cell Tissue Res. 2018 Aug 15. doi: 10.1007/s00441-018-2881-3. [Epub ahead of print] Review.

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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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Strategy for marker-based differentiation of pro- and anti-inflammatory macrophages using matrix-assisted laser desorption/ionization mass spectrometry imaging. Analyst. 2018 Jul 20. doi: 10.1039/c8an00659h. [Epub ahead of print]

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Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression. J Mol Cell Cardiol. 2018 Jul;120:31-41. doi: 10.1016/j.yjmcc.2018.05.010. Epub 2018 May 16.

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Role of CD40 and ADAMTS13 in von Willebrand factor-mediated endothelial cell-platelet-monocyte interaction. Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5556-E5565. doi: 10.1073/pnas.1801366115. Epub 2018 May 23.

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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]

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Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons. J Neurochem. 2018 Jun 4. doi: 10.1111/jnc.14479. [Epub ahead of print]

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The lncRNA CASC9 and RNA binding protein HNRNPL form a complex and co-regulate genes linked to AKT signaling. Hepatology. 2018 May 23. doi: 10.1002/hep.30102. [Epub ahead of print]

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Early Blood-Brain Barrier Disruption in Ischemic Stroke Initiates Multifocally Around Capillaries/Venules. Stroke. 2018 Jun;49(6):1479-1487. doi: 10.1161/STROKEAHA.118.020927. Epub 2018 May 14.

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Impact of carbonylation on glutathione peroxidase-1 activity in human hyperglycemic endothelial cells. Redox Biol. 2018 Jun;16:113-122. doi: 10.1016/j.redox.2018.02.018. Epub 2018 Mar 1.

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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 Mar 7. doi: 10.1152/ajprenal.00633.2017. [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