%0 Generic
%A Wójtowicz, Agnieszka
%D 2008
%F heidok:8701
%K Zyxin , Signaltransduktion , Endothelzellen , Gefäßwandumbauzyxin , remodelling , mechanotransduction , vessels , ANP
%R 10.11588/heidok.00008701
%T The focal adhesion protein zyxin mediates wall tension-induced signalling in vascular cells
%U https://archiv.ub.uni-heidelberg.de/volltextserver/8701/
%X Hypertrophy in conduit and hyperplasia in resistance-sized arteries is the clinically visible outcome of a supra-physiological pressure-induced stretching of endothelial and smooth muscle cells, e.g. in arterial hypertension. This adaptive remodelling of the vessel wall in response to mechanical overload results in the fixation of vascular resistance at devoted levels and, therefore, is a major contributor to coronary heart disease, dilated cardiomyopathy and stroke. Although phenomenologically characterized in detail, the signal transduction pathways underlying the stretchinduced shift in vascular gene expression and, consecutively, long-term phenotype changes of endothelial as well as smooth muscle cells are still poorly understood. In this thesis, the first specifically mechanotransducing protein in endothelial cells could be defined with the focal adhesion protein zyxin. Moreover, it could be shown that zyxin after nuclear translocation orchestrates stretch-induced gene expression in a highly complex way. By comparing isolated perfused arteries from wild type and zyxin-deficient mice, it could be further demonstrated that zyxin plays a decesive role in maintaining vascular structure and function under conditions of high perfusion pressure. Supra-physiological levels of stretch caused a dissociation of zyxin from focal adhesions in endothelial cells. This event was mediated by the consecutive stretchinduced release and coordinated action of endothelin-1 (ET-1) and atrial natriuretic peptide (ANP). The ET-1-mediated release of ANP resulted in a presumably A-type natriuretic peptide receptor-mediated, cGMP-induced activation of protein kinase G, which in turn phosphorylated zyxin, thereby facilitating its dissociation from the focal adhesions and accumulation in the nucleus. This complex stretch-induced signalling cascade described herein for the first time for endothelial cells, closely resembles the multi-cellular events preceding the cardiac release of ANP. Thus, endothelial cells are not only able to sense stretch, but also specifically transduce and respond to mechanical overload by activating the newly characterized mechanotransducer zyxin. Moreover, the first systematic genome-wide microarray analysis of human endothelial and mouse vascular smooth muscle cells revealed a highly complex – albeit similar – response of these cells to mechanical overload. Against the background of the long known effects of chronic stretch in the arterial system, namely hypertension, the microarray results obtained are highly suggestive. In both cell types, more than 600 gene products were differentially expressed in response to cyclic stretch. These could be grouped into in several well-defined cellular pathways that are known to be crucial for the development of hypertrophy and/or hyperplasia in the course of vascular remodelling. Most interesting, a parallel microarray analysis comparing zyxindeficient stretched endothelial and smooth muscle cells with their zyxin-expressing counterparts revealed that zyxin is fundamental for the changes in gene expression preceding stretch-induced vascular remodelling processes. Zyxin suppression would thus result in the inhibition of pro-hypertrophic pathways, e.g. by a shift towards proapoptotic gene expression, but also may affect signalling pathways involved in normal vascular function. Finally, by using freshly isolated perfused segments of the mouse femoral artery from wild type and zyxin-deficient mice, it could be demonstrated that vascular function depends on the presence of zyxin. Although the phenotype of zyxin-deficient mice is mild in young animals, vascular function and structure is strongly impaired in aged mice. Vasoconstriction and, thus, the ability for the regulation of flow resistance, is strongly diminished in zyxin-deficient animals. This effect most probably occurs due to missing zyxin-induced expression. The crucial function of zyxin in vascular physiology could be further substantiated by initial experiments employing the DOCA-salt hypertension model in wild type and zyxin-deficient mice. In conclusion, besides thoroughly analyzing stretch-induced zyxin signalling and gene expression in vascular cells, this thesis provides some interesting insights into the pathophysiological relevance of this molecule, which in the future may be decisive to develop novel therapeutic strategies against hypertension-induced alterations in vascular structure and function.