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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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Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5. FASEB J. 2017 Dec 5. pii: fj.201700384RR. doi: 10.1096/fj.201700384RR. [Epub ahead of print]

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Modulation of glutathione peroxidase activity by age-dependent carbonylation in glomeruli of diabetic mice. J Diabetes Complications. 2017 Nov 22. pii: S1056-8727(17)31094-2. doi: 10.1016/j.jdiacomp.2017.11.007. [Epub ahead of print]

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Sensitive mass spectrometric assay for determination of 15-deoxy-Δ12,14-prostaglandin J2 and its application in human plasma samples of patients with diabetes. Anal Bioanal Chem. 2017 Nov 16. doi: 10.1007/s00216-017-0748-1. [Epub ahead of print]

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Role of protein carbonylation in diabetes. J Inherit Metab Dis. 2017 Nov 6. doi: 10.1007/s10545-017-0104-9. [Epub ahead of print]

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AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome. Mol Ther Nucleic Acids. 2017 Dec 15; 9: 69–79. Epub 2017 Sep 20. doi: 10.1016/j.omtn.2017.08.014

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Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift. J Enzyme Inhib Med Chem. 2017 Dec;32(1):1102-1110. doi: 10.1080/14756366.2017.1355793.

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Transcription factor decoy technology: a therapeutic update. Biochem Pharmacol. 2017 Nov 15;144:29-34. doi: 10.1016/j.bcp.2017.06.122. Epub 2017 Jun 19. Review.

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Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus. J Cereb Blood Flow Metab. 2017 Nov 3; 271678X17740091. doi: 10.1177/0271678X17740091

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Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells. Stem Cell Res Ther. 2017 Oct 16;8(1):229. doi: 10.1186/s13287-017-0681-4.

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Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory. EMBO J. 2017 Sep 15;36(18):2770-2789. doi: 10.15252/embj.201696369. Epub 2017 Aug 8


Institute of
Physiology and Pathophysiology

Heidelberg University

Im Neuenheimer Feld 326

69120 Heidelberg

Germany

Phone:+49 6221 54-4056
Fax:+49 6221 54-6364
E-mail:susanne.bechtel@
physiologie.uni-heidelberg.de