Download Mechanical Forces in the vascular system

Mechanical Forces in the vascular system
Danijela Heide, Simone Pöschel, Agnieszka Wojtowicz and Marco Cattaruzza
Mechanical stimuli, namely fluid shear stress (on endothelial cells) and Laplace wall tension
(endothelial and smooth muscle cells), play a major role in the regulation of blood flow and long term
homeostasis of the vascular system.
fluid shear stress:
τ = 4ηQ/r³π
wall tension (Laplace)
σ∼ ptm × r/d
Figure 1: Principal forces modulating vessel tone and homeostasis. Whereas fluid shear
stress (τ) can be defined by blood viscosity (η), laminar flow (Q) and is inversely
proportional to the vessel radius (r), Laplace wall tension (σ) depends on transmural
pressure (ptm), radius and is inversely correlated to the vessel wall thickness (d).
As both forces inversely depend on the vessel diameter, it is comprehensible that they play a
functionally antagonistic role in regulating vessel tone and, thus, blood flow. This is well understood
down to molecular mechanisms involving, e.g., nitric oxide (NO) and the vasoconstrictor peptide
endothelin-1. However, although long term effects of laminar shear stress and wall tension on vessel
wall structure, e.g., in the case of pressure-induced arterial hypertrophy/hyperplasia in hypertensive
patients are well documented, molecular mechanisms of these processes are virtually not understood.
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.
In the first project we analyse the mechanism 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 (1, 2), 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 (3). 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).
FA
?
(A)NP
P
zyx
P
NPR-A/B
zyx
Mat3 ?
?
PyPu-box PyPu-box
Figure 2: Putative mechanisms of zyxin (zyx) activation and nuclear function in response
to increased wall tension. Focal adhesion points (FA seem to activate the release of
natriuretic peptides (ANP) from endothelial cells. (A)NP then causes phosphorylation of
zyxin (and/or associated proteins), the protein translocates to the nucleus and initiates
directly or indirectly wall tension-induced gene expression eventually leading to
phenotype changes of endothelial and smooth muscle cells.
The second project deals with the mechanisms of fluid shear stress-induced up-regulation of the
expression of the endothelial nitric oxide synthase (NOS-3). 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 nos-3 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 (4) and rheumatoid arthritis (5). Currently we try to understand how
nos-3 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 stabilize NOS-3 expression independently from laminar shear
stress and, thus, prevent endothelial dysfunction and, consecutively, the development of
atherosclerosis.
Literature:
1)
2)
3)
4)
5)
Cattaruzza M, Eberhardt I, Hecker M (2001). Mechanosensitive transcription factors
involved in endothelin B receptor expression. J Biol Chem 276, 36999-37003.
Cattaruzza M, Berger MM, Ochs M, Fayyazi A, Füzesi L, Richter J, Hecker M (2002).
Deformation-induced endothelin B receptor-mediated smooth muscle cell apoptosis is
matrix-dependent. Cell Death Differ 9, 219-226.
Cattaruzza M, Lattrich C, Hecker M (2004). The focal adhesion protein zyxin is a
mechanosensitive modulator of gene expression in vascular smooth muscle cells.
Hypertension 43, 726-730.
Cattaruzza M, Tomasz J. Guzik, Wojciech Słodowski, Ay egül Pelvan, Jürgen Becker,
Martin Halle, Arnd B. Buchwald, Keith M. Channon, Markus Hecker (2004). Shear stress
insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for
coronary heart disease. Circ Res 95:841-847.
Melchers I, Blaschke S, Hecker M , Cattaruzza M (2006). -786C/T Single Nucleotide
Polymorphism in the Promoter of the Endothelial Nitric Oxide Synthase Gene: Insensitivity
to Physiological Stimuli as a Risk Factor for Rheumatoid Arthritis. Arthritis and Rheumatism
(in press).