Meibergdreef 9 1105 AZ Amsterdam

Home > Projects > ESR 10

Zyxin control of stretch-induced arterial remodelling.

 

Description

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.

Publications

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.

  • Text Hover

Ph.D student / post-doc

Taslima Nahar

 

Principal Investigator

Prof. Markus Hecker