Role of zyxin family members in hypertension-induced arterial remodelling

• Applicant: Professor Markus Hecker, Ph.D.
• Subject Area: Anatomy and Physiology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329853703

Chronic arterial hypertension increases wall tension in both large conduit and small resistance-sized arteries. Continuous stretch, especially of the vascular smooth muscle cells (VSMC), leads to maladaptive remodelling of the vessel wall (hypertrophy in the former and hyperplasia in the latter type of arteries) including reorganization of the extracellular matrix, stiffening the conduit arteries and increasing peripheral resistance. The manifested arterial hypertension overloads the heart, especially the left ventricle, with the risk of cardiac hypertrophy and possibly cardiac insufficiency. Work of our group shows that in highly stretched endothelial cells (EC) and VSMC zyxin, a protein localized in focal adhesions, translocates to the nucleus where it controls expression of 70% and 90% of the mechanosensitive genes, respectively. In EC it acts as a mechanoresponsive transcription factor, in VSMC it changes actin dynamics and the RhoA-MRTF-A signalling pathway. VSMC isolated from the aorta of 3 months old global zyxin knockout mice show an activated synthetic phenotype. In vivo, these mice develop a phenotype only when hypertension is experimentally induced at the age of 6-18 months. The cardiac phenotype, which is comparable to restrictive cardiomyopathy in humans, can already be seen in young animals. The vascular phenotype, which corresponds to that of VSMC from zyxin-deficient mice in vitro, solely occurs in the oldest group and is only weakly developed. Recent studies suggest that this is not due to the loss of zyxin but to an age-dependent decline of its close relative, lipoma preferred partner (LPP), the overexpression of which reverses cultured zyxin-null VSMC into the dormant contractile phenotype. VSMC isolated from the aorta of global LPP knockout mice show an activated synthetic phenotype, whereas LPP knockout mice in vivo, in contrast to zyxin knockout mice, do not show a cardiac phenotype in any phase of life, but a pronounced vascular phenotype, especially in 12-month old animals. The latter manifests itself only in the face of experimental hypertension primarily in the descending aorta and, in the middle third of the 21-day observation period, resembles an exacerbated Marfan syndrome with a highly unstable vessel wall. Since LPP, unlike zyxin, is not expressed in the endothelium of both conduit and resistance-sized arteries from wild-type mice, the renewal application focuses on the role of LPP in the VSMC in the context of hypertension-induced maladaptive remodelling as follows: (1) Verification of the vascular phenotype of the global LPP knockout mice in the already generated tamoxifen-inducible VSMC-specific LPP knockout mice. (2) Characterization of the underlying cellular and molecular mechanisms with a focus on reduced contractility in the smaller and destabilization of the extracellular matrix in the larger arteries, respectively. (3) Confirmation of the putative phenotype-stabilising role of LPP in human VSMC.

• DFG Programme: Research Grants