Lin11-Isl1-Mec3 Domain Proteins as Mechanotransducers in Endothelial and Vascular Smooth Muscle Cells

Abstract

Arterial hypertension is the leading risk factor for cardiovascular morbidity and mortality worldwide. However, little is known about the cellular mechanisms underlying it. In small arteries and arterioles, a chronic increase in blood pressure raises wall tension and hence stretches, namely, the medial vascular smooth muscle cells (VSMC) but also endothelial cell (EC) to cell contacts. Initially compensated by an increase in vascular tone, the continuous biomechanical strain causes a prominent change in gene expression in both cell types, frequently driving an arterial inward remodeling process that ultimately results in a reduction in lumen diameter, stiffening of the vessel wall, and fixation of blood pressure, namely, diastolic blood pressure, at the elevated level. Sensing and propagation of this supraphysiological stretch into the nucleus of VSMC and EC therefore seems to be a crucial step in the initiation and advancement of hypertension-induced arterial remodeling. Focal adhesions (FA) represent an important interface between the extracellular matrix and Lin11-Isl1-Mec3 (LIM) domain-containing proteins, which can translocate from the FA into the nucleus where they affect gene expression. The varying biomechanical cues to which vascular cells are exposed can thus be rapidly and specifically propagated to the nucleus. Zyxin was the first protein described with such mechanotransducing properties. It comprises 3 C-terminal LIM domains, a leucine-rich nuclear export signal, and N-terminal features that support its association with the actin cytoskeleton. In the cytoplasm, zyxin promotes actin assembly and organization as well as cell motility. In EC, zyxin acts as a transcription factor, whereas in VSMC, it has a less direct effect on mechanosensitive gene expression. In terms of homology and structural features, lipoma preferred partner is the nearest relative of zyxin among the LIM domain proteins. It is almost exclusively expressed by smooth muscle cells in the adult, resides like zyxin at FA but seems to affect mechanosensitive gene expression indirectly, possibly via altering cortical actin dynamics. Here, we highlight what is currently known about the role of these LIM domain proteins in mechanosensing and transduction in vascular cells.

Transcriptional and Epigenetic Factors Associated with Early Thrombosis of Femoral Artery Involved in Arteriovenous Fistula

“…Vascular stiffness, mainly arterial stiffness, plays a critical role in hypertension, involving a change in the gene expression and phenotype of VSMCs and ECs and their focal contacts. In ECs and VSMCs, Lin11-Isl1-Mec3 (LIM) domain-containing proteins play a critical role as mechanotransducers [ 34 ] and hemodynamic changes occur after AVF creation and contribute to AVF maturation and/or failure. Investigating the role of Isl1, which was found to be activated in this study, will be of significance.…”

The role of zyxin in signal transduction and its relationship with diseases

“…In the process of mechanical signal transduction, zyxin is considered a significant participant ( Beckerle, 1986 ; Beckerle, 1997 ; Nix and Beckerle, 1997 ; Drees et al, 1999 ; Yoshigi et al, 2005 ; Hoffman et al, 2006 ; Hirata et al, 2008a ; Hirata et al, 2008b ). Zyxin can directly and indirectly control the expression of mechanically sensitive genes ( Sporkova et al, 2021 ), playing a crucial role in mechanical sensing pathways. YAP is a key nuclear transcription factor closely associated with mechanical signals and cell morphology.…”

“…It can interact with Bcl-2, affecting cell survival and anti-apoptotic ability (Bernusso, 2013). It can also interact with Src kinase, enhancing or inhibiting cell proliferation (Sporkova et al, 2021). Zyxin can also interact with various transcription factors, such as 6E6 (Degenhardt and Silverstein, 2001), HNF-1β (Hiesberger et al, 2004), CARP-1 (Hervy et al, 2010), Xanf1 (Martynova et al, 2008), ZNF384 (Janssen and Marynen, 2006), CBP (Youn et al, 2013), influencing various biological functions of the cell (Table 1).…”