The focal adhesion molecule zyxin specifically translocate to the nucleus of vascular cells in response to stretch1,2 or hypertension3. In the nucleus, the protein orchestrates expression of a majority of stretch-/pressure-induced genes2 among which mRNAs encoding for matrix proteins and ECM modifying enzymes are prominent. Aged zyxin-deficient mice show a reorientation of the arterial smooth muscle cells (SMCs) in response to hypertension, associated with a more pronounced pressure-induced passive distension and a failure to up-regulate blood pressure.
Hypothesis: We postulate that adult zyxin-deficient mice develop a severe deficit in arterial contractility due to a marked alteration in matrix composition. The stretch-sensitive transcription factor zyxin therefore must have a major impact on the control of vascular SMC phenotype.
Objectives: The ESR will focus on the role of zyxin-controlled ECM proteins and matrix-modifying enzymes in pressure-induced vascular remodelling. In vitro experiments will focus on migration, proliferation, contractility and expression of phenotype-discriminating gene products (contractile vs. synthetic) in murine arterial cultured SMCs following loss of function (siRNA-based knockdown) or gain of function (transient overexpression) of distinct matrix proteins/enzymes. Based on these results, composition and mechanical properties of the basal membrane and extracellular matrix in the media of different arteries and arterioles of wild type and zyxin-deficient animals will be compared with and without prior induction of hypertension (DOCA-salt model).
Training: The ESR will be trained in all relevant in vitro as well as in vivo phenotyping methods including telemetry-based blood pressure recordings and high resolution ultrasound imaging of small arteries/arterioles by using the Vevo 2100 system with partner VIS. In addition, he/she will train 2 months with partner WWU on ECM proteins.
1 Cattaruzza M. Hypertension 2004; 43:726-730. 2 Wójtowicz A. Circ Res 2010; 107 :898-902. 3 Babu SS. Science Sig 2012; in press.
Ghosh, S., Kollar, B., Nahar, T., Suresh Babu, S., Wojtowicz, A., Sticht, C., Gretz, N., Wagner, A.H., Korff, T., & Hecker, M. (2015). Loss of the mechanotransducer zyxin promotes a synthetic phenotype of vascular smooth muscle cells. J. Am. Heart Assoc., 4:e001712. doi: 10.1161/JAHA.114.001712.
Ph.D student / post-doc
Prof. Markus Hecker