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Institute of Physiology and Pathophysiology

Hecker Group

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Group Members

Vascular blood flow and pressure act on endothelial as well as on smooth muscle cells. Not surprisingly, these mechanical forces are a major factor in the regulation of vascular perfusion as well as, in the long run, vascular cell phenotype and vessel structure.

Our group tries to further our understanding of how fluid shear stress and wall tension act on vascular cells, and what consequences can be expected under supra-physiological conditions, e.g. in hypertension. To this end we focus on two projects: a) the role of zyxin, a protein shuttling between the cytoskeleton and the nucleus, in pressure-induced vascular remodelling, and b) the expression of variants of the human endothelial nitric oxide synthase gene nos3 in response to fluid shear stress.

Background: Mechanical Forces in the Vascular System

In the blood vessel mechanical stimuli, mainly generated through fluid shear stress acting on endothelial cells, and Laplace wall tension affecting both endothelial and smooth muscle cells, play a major role in the regulation of blood flow and long term homeostasis of the vascular system (Figure 1).

Figure 1: Principal forces modulating vessel tone and vascular homeostasis. While fluid shear stress (τ) is defined by blood viscosity (η), laminar flow (Q), and the reciprocal of the vessel radius (r), Laplace wall tension (σ) depends on transmural pressure (ptm), radius (r), and the inverse of the vessel wall thickness (d).

As both forces inversely depend on the vessel diameter,  they play a functionally antagonistic role in regulating vessel tone and, thus, blood flow. This is well understood down to its molecular mechanisms, which rely on, e.g. nitric oxide (NO) and the vasoconstrictor peptide endothelin-1. However, although long-term effects of altered laminar shear stress and wall tension on vessel wall structure, as it occurs in, e.g. pressure-induced arterial hypertrophy/hyperplasia in hypertensive patients, are well documented, the signalling pathways underlying these processes are not characterised yet. Our group concentrates on two projects analysing the effects of wall tension and fluid shear stress on gene expression and phenotype regulation in endothelial and vascular smooth muscle cells.

Zyxin as a Mechanotransducer in Vascular Cells

In this project we analyse the mechanism of how supra-physiological levels of wall tension lead to phenotype changes in vascular cells in vitro and in situ. Although common signal transduction pathways play a role in the vascular response to increases in wall tension, a major event in this process is the wall tension/pressure-induced translocation of the cytoskeletal protein zyxin followed by zyxin-mediated changes in gene expression. This is the first description of a protein specific for mechanotransduction in vascular cells. Currently we analyse how wall tension activates zyxin and what the mechanisms of tension-induced zyxin-mediated gene expression are (Figure 2).

Figure 2: Zyxin in static and stretched aortic endothelial cells. Zyxin (red) is localised in the focal adhesions (FA; yellow) of quiescent cells. Cyclic stretch causes translocation of zyxin to the nuclei  (Nu; blue). Paxillin (green) colocalises with zyxin exclusively in focal  adhesions but not in the nucleus (after stretch). (confocal image)

Shear Stress-Dependent Regulation of NOS3 Expression in Endothelial Cells

The second project deals with the mechanisms of fluid shear stress-induced up-regulation of the expression of the endothelial nitric oxide synthase (NOS3). The enzyme as well as its high expression due to shear stress are major factors in maintaining endothelial function. This statement can be highlighted by the fact that a frequent variant of the human nos3 gene promoter, a single nucleotide exchange at position -786 is insensitive to fluid shear and that this variant constitutes a risk factor for developing coronary heart disease and rheumatoid arthritis. Currently we try to understand how nos3 gene expression normally is increased in response to laminar shear stress and how the exchange of a single nucleotide can lead to insensitivity to shear and other inducing factors. Answers to both questions might lead to a strategy to stabilise NOS3 expression independently from laminar shear stress and, thus, prevent endothelial dysfunction and, consecutively, the development of atherosclerosis.


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