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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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Methylglyoxal evokes acute Ca2+ transients in distinct cell types and increases agonist-evoked Ca2+ entry in endothelial cells via CRAC channels. Cell Calcium. 2019 Mar;78:66-75. doi: 10.1016/j.ceca.2019.01.002. Epub 2019 Jan 9.

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EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke. Acta Neuropathol Commun. 2019 Feb 5;7(1):15. doi: 10.1186/s40478-019-0669-7.

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Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer's disease amyloidosis. PLoS One. 2019 Jan 15;14(1):e0209228. doi: 10.1371/journal.pone.0209228. eCollection 2019.

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Medikamentöse Varikosetherapie aus der Perspektive experimenteller Modelle. Praxis (Bern 1994). 2019 Jan;108(1):31-36. doi: 10.1024/1661-8157/a003147.

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Selective vulnerability of αOFF retinal ganglion cells during onset of autoimmune optic neuritis. Neuroscience. 2018 Nov 21;393:258-272. doi: 10.1016/j.neuroscience.2018.07.040. Epub 2018 Aug 1.

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The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function. FASEB J2018 Nov;32(11):6159-6173. Epub 2018 Jun 7.

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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]

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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