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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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Early appearance and spread of fast ripples in the hippocampus in a model of cortical traumatic brain injury. J Neurosci. 2018 Oct 17;38(42):9034-9046. doi: 10.1523/JNEUROSCI.3507-17.2018. Epub 2018 Sep 6.

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High-fat diet suppresses the positive effect of creatine supplementation on skeletal muscle function by reducing protein expression of IGF-PI3K-AKT-mTOR pathway. PLoS One. 2018 Oct 4;13(10):e0199728. doi: 10.1371/journal.pone.0199728. eCollection 2018.

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Alcohol reduces muscle fatigue through atomistic interactions with nicotinic receptors. Commun Biol. 2018 Oct 3;1:159. doi: 10.1038/s42003-018-0157-9. eCollection 2018.

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Possible neurotoxicity of the anesthetic propofol: evidence for the inhibition of complex II of the respiratory chain in area CA3 of rat hippocampal slices. Arch Toxicol. 2018 Oct;92(10):3191-3205. doi: 10.1007/s00204-018-2295-8. Epub 2018 Aug 24.

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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 Oct 1;315(4):F861-F869. doi: 10.1152/ajprenal.00633.2017. Epub 2018 Mar 7.

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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 Sep 10;143(18):4273-4282. doi: 10.1039/c8an00659h. Epub 2018 Jul 20.

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Recent advances in hippocampal structure and function. Cell Tissue Res. 2018 Sep;373(3):521-523. doi: 10.1007/s00441-018-2913-z. Epub 2018 Aug 20. doi: 10.1007/s00441-018-2913-z. Editorial. No abstract available.

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Electrical coupling between hippocampal neurons: contrasting roles of principal cell gap junctions and interneuron gap junctions. Cell Tissue Res. 2018 Sep;373(3):671-691. doi: 10.1007/s00441-018-2881-3. Epub 2018 Aug 15. Review.

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Synaptic entrainment of ectopic action potential generation in hippocampal pyramidal neurons. J Physiol. 2018 Aug 24. doi: 10.1113/JP276720. [Epub ahead of print]

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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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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.

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Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons. J Neurochem. 2018 Aug;146(4):446-458. doi: 10.1111/jnc.14479. Epub 2018 Aug 1.

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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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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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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]


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