TY  - JOUR
A1  - Gotschy, Alexander
A1  - Bauer, Wolfgang R.
A1  - Winter, Patrick
A1  - Nordbeck, Peter
A1  - Rommel, Eberhard
A1  - Jakob, Peter M.
A1  - Herold, Volker
T1  - Local versus global aortic pulse wave velocity in early atherosclerosis: An animal study in ApoE\(^{-/-}\) mice using ultrahigh field MRI
JF  - PLoS ONE
N2  - Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE\(^{-/-}\) and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE\(^{-/-}\) and WT mice were determined for global and local PWV measurements (global PWV: ApoE\(^{-/-}\): 2.7 ±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE\(^{-/-}\): 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R\(^2\) = 0.75, P<0.01), implying a widely uniform arterial elasticity.
In ApoE\(^{-/-}\) animals, however, no significant correlation between individual local and global PWV was present (R\(^2\) = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel
phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions.
KW  - MRI
KW  - Atherosclerosis
KW  - Aorta
KW  - Stiffness
KW  - Measurement
KW  - Time measurement
KW  - Magnetic resonance imaging
KW  - Mouse models
KW  - Systole
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171824
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Lohse, Christian
A1  - Bock, Andreas
A1  - Maiellaro, Isabella
A1  - Hannawacker, Annette
A1  - Schad, Lothar R.
A1  - Lohse, Martin J.
A1  - Bauer, Wolfgang R.
T1  - Experimental and mathematical analysis of cAMP nanodomains
JF  - PLoS ONE
N2  - In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear. In this paper, using fusion proteins of cAMP FRET-sensors and PDEs in living cells, we provide direct experimental evidence that the cAMP concentration in the vicinity of an individual PDE molecule is below the detection limit of our FRET sensors (<100nM). This cAMP gradient persists in crude cytosol preparations. We developed mathematical models based on diffusion-reaction equations which describe the creation of nanocompartments around a single PDE molecule and more complex spatial PDE arrangements. The analytically solvable equations derived here explicitly determine how the capability of a single PDE, or PDE complexes, to create a nanocompartment depend on the cAMP degradation rate, the diffusive mobility of cAMP, and geometrical and topological parameters. We apply these generic models to our experimental data and determine the diffusive mobility and degradation rate of cAMP. The results obtained for these parameters differ by far from data in literature for free soluble cAMP interacting with PDE. Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.
KW  - fluorescence resonance energy transfer
KW  - yellow fluorescent protein
KW  - radii
KW  - adenylyl cyclase signaling cascade
KW  - cell fusion
KW  - cytosol
KW  - isoproterenol
KW  - absorption
KW  - cyclic nucleotides such as cyclic adenosine monophosphate
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170972
VL  - 12
IS  - 4
ER  -