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Institute of Physiology and Pathophysiology

Korff Group

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Group Members

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.

     

   

For instance, detrimental hypertension-induced arterial remodeling or varicose vein formation are associated with or elicited by a chronic increase in biomechanical wall stress.

  

   

On the experimental level, our portfolio includes multiple in vitro and in vivo techniques supporting the 3R-principle of animal welfare (Replace, Reduce, Refine): In vitro, we utilize advanced 2D/3D cell culture techniques (including vascular organoids) allowing to expose cultured human or mouse vascular endothelial and smooth muscle cells to various environmental stressors (Replacement models). Corresponding experimental approaches are utilized for basic mechanistic studies which help us to identify new stress-regulated target molecules and/or mechanisms. In addition, we investigate cellular responses in perfused isolated mouse arteries and veins in order to closely mimic the in vivo environment (Reduction). In vivo, we apply various models in combination with state-of-the-art imaging methods to identify cell specific phenotype changes. We also take advantage of (low burden) mouse auricle artery/vein ligation models (Refinement), which allow for the easy visualization and measurement of changes in the vascular architecture and the local transdermal application of drugs.

   

   

Embedded in the aforementioned general context, our group currently investigates 1) the impact of vascular NFAT5 (nuclear factor of activated T-cells 5) on lung function and responses to hypoxia, 2) mechanisms of smooth muscle foam cell formation and 3) G-protein-mediated mechanisms contributing to hypertension-induced vascular remodeling processes.

   

1) Impact of vascular NFAT5 on lung function and responses to hypoxia

 

The lung forms a specialized border for gas exchange and may rapidly respond to local hypoxia by adapting its perfusion for optimized blood oxygenation. However, chronic hypoxia that is associated with many pulmonary diseases (e.g. fibrosis or chronic obstructive pulmonary disease, COPD) promotes irreversible structural remodeling and subsequent lung dysfunction. We observed that NFAT5 is expressed in vascular endothelial and smooth muscle cells of the hypoxic lung and that its loss in smooth muscle cells inhibits muscularization of pulmonary arteries as well as right heart hypertrophy.

Our studies on that topic explore the role of NFAT5 in controlling structural changes and inflammatory responses of the hypoxic lung. Specifically, the NFAT5-dependent modification of the vascular transcriptome and its impact on pulmonary artery remodeling processes is investigated.


2) Regulation of VSMC foam cell development

 

Atherosclerosis is considered a cholesterol storage disorder characterized by the accumulation of cholesterol in the arterial wall leading to lumen narrowing due to plaque growth and thereby increasing the risk for myocardial infarction or stroke. Atherosclerotic plaques consist to a large extent of lipid-laden foam cells. In recent years, it has been discovered that these cells are mainly derived from vascular smooth muscle cells (VSMCs). While a considerable amount of proteins have been identified to regulate the VSMC phenotype, significantly less is known about the control of VSMC foam cell formation. The thickening of the vessel wall, as it occurs in arteriosclerosis or vessel injury, is caused by active, proliferating and migrating medial VSMCs in the intima layer which was identified as an important determinant of atherosclerotic plaque formation. To achieve this, the activity of transcription factors controlling the VSMC activation state/phenotype, such as activator protein-1, myocardin or NFAT5, has to change. From a clinical point of view, reducing lipid accumulation during the early phase of arteriosclerotic plaque formation thus poses as an attractive strategy to prevent cardiovascular complications. Therefore, we seek to identify the underlying mechanisms leading to VSMC foam cell formation in atherosclerosis.

 

 

 

3) G-Protein-dependent control of vascular remodeling

 

A pivotal feature of arteries is their capacity to adapt the architecture of the vascular wall to alterations in the environment. For instance, a chronic increase in blood flow promotes arterial dilation while elevated blood pressure results in thickening and stiffening of the arterial wall which elevates blood pressure even further.

 

This context-dependent structural arterial remodeling is caused by activation of medial vascular smooth muscle cells (VSMCs) triggered by biomechanical or neurohumoral stimuli. In this context, G protein signaling is rate-limiting for signal transduction of both kinds of stimuli to orchestrate phenotype changes of arterial VSMCs. Their activity is balanced by a family of proteins known as regulators of G-protein signaling (RGS).

 

We recently reported that biomechanical stress is sufficient to increase cytoplasmic abundance of RGS5 in VSMCs which is required to promote arterial growth in mice. RGS5 is an endogenous inhibitor of Gαq/11 and Gαi/o signaling which appears to be rate-limiting for activation of RhoA – a critical determinant of the VSMC phenotype during biomechanically-induced arterial remodeling processes.

 
This project aims at (i) delineating the mechanism and influence of RGS5-mediated G-protein blockade on contractile responses and architecture of arteries as well as the outcome of arterial remodeling processes and (ii) exploring the regulation and functional contribution of other RGS proteins to G-protein- and hypertension-induced VSMC responses and arterial remodeling.

 

Selcted Publications

Arnold C, Feldner A, Zappe M, Komljenovic D, De La Torre C, Ruzicka P, Hecker M, Neuhofer W, Korff T. 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]

Zappe M, Feldner A, Arnold C, Sticht C, Hecker M, Korff T. 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.

Arnold C, Demirel E, Feldner A, Genové G, Zhang H, Sticht C, Wieland T, Hecker M, Heximer S, Korff T. Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5. FASEB J. 2018 Apr;32(4):2021-2035. doi: 10.1096/fj.201700384RR. Epub 2018 Jan 5.

Schröder H, Komljenovic D, Hecker M, Korff T. Transdermal drug targeting and functional imaging of tumor blood vessels in the mouse auricle. FASEB J. 2016 Feb;30(2):923-32. doi: 10.1096/fj.15-279240. Epub 2015 Nov 6.

Hödebeck M, Scherer C, Wagner AH, Hecker M, Korff T. TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells. Front Physiol. 2014 Dec 3;5:467. doi: 10.3389/fphys.2014.00467. eCollection 2014.

Arnold C, Feldner A, Pfisterer L, Hödebeck M, Troidl K, Genové G, Wieland T, Hecker M, Korff T. RGS5 promotes arterial growth during arteriogenesis. EMBO Mol Med. 2014 Jun 27;6(8):1075-89. doi: 10.15252/emmm.201403864.

Scherer C, Pfisterer L, Wagner AH, Hödebeck M, Cattaruzza M, Hecker M, Korff T. Arterial wall stress controls NFAT5 activity in vascular smooth muscle cells. J Am Heart Assoc. 2014 Mar 10;3(2):e000626. doi: 10.1161/​JAHA.113.000626.

Pfisterer L, Feldner A, Hecker, M, Korff T. Hypertension impairs myocardin function - a novel mechanism facilitating arterial remodeling. Cardiovasc Res. 2012 Oct 1;96(1):120-9. Epub 2012 Jul 26.

Korff T, Kimmina S, Martiny-Baron G, Augustin HG. Blood vessel maturation in a 3-dimensional spheroidal coculture model: direct contact with smooth muscle cells regulates endothelial cell quiescence and abrogates VEGF responsiveness. FASEB J. 2001 Feb;15(2):447-57.

Korff T, Augustin HG. Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol. 1998 Nov 30;143(5):1341-52.


Recent Publications

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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 Jun 19. doi: 10.1161/CIRCRESAHA.118.313820. [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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Marfan syndrome: A therapeutic challenge for long-term care. Biochem Pharmacol. 2019 Jun;164:53-63. doi: 10.1016/j.bcp.2019.03.034. Epub 2019 Mar 27.

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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 May 16. pii: S1525-0016(19)30222-9. doi: 10.1016/j.ymthe.2019.05.008. [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]

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Chronic hypoxia changes gene expression profile of primary rat carotid body cells: consequences on the expression of NOS isoforms and ET-1 receptors. Physiol Genomics. 2019 Apr 1;51(4):109-124. doi: 10.1152/physiolgenomics.00114.2018. Epub 2019 Mar 1.

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Determination of the Maximum Velocity of Filaments in the in vitro Motility Assay. Front Physiol. 2019 Mar 27;10:289. doi: 10.3389/fphys.2019.00289. eCollection 2019.

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Priming of microglia with IFN-γ slows neuronal gamma oscillations in situ. Proc Natl Acad Sci U S A. 2019 Feb 19. pii: 201813562. doi: 10.1073/pnas.1813562116. [Epub ahead of print]

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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]


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