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.
Highlights
Blood vessels are constantly exposed to mechanical forces
LIM domain proteins, such as zyxin and lipoma preferred partner (LPP) act, depending on the type of vascular cell, as mechanotransducers directly or indirectly (LPP) propagating the biomechanical stress signal into the nucleus and a change in gene expression that aims at maintaining the cells in a quiescent state
While expression of LPP seems to be restricted to vascular smooth muscle cells (SMC) in the adult, zyxin is highly abundant in endothelial cell (EC)
Summary
Blood vessels are constantly exposed to mechanical forces. The physical properties of the flowing blood are sensed by the endothelial cells (EC), which, under conditions of laminar flow, adapt both functionally and structurally to alterations in unidirectional shear stress. When arteries are chronically exposed to elevated circumferential wall tension, such as during hypertension, the quiescent contractile phenotype of the vascular SMC changes to secretory and growth promoting (Rensen et al, 2007; Saleh et al, 2016) This chronic increase in blood pressure frequently drives an initially adaptive inward remodeling process in small arteries and arterioles that eventually becomes maladaptive due to narrowing of the lumen and stiffening of the ECM. Whereas the function of zyxin in vascular cells, especially in EC and vascular SMC, has already been well characterized (Cataruzza et al, 2004; Wójtowicz et al, 2010), the mechanotransducer role of LPP, the expression of which is restricted to SMC, in particular vascular SMC (Gorenne et al, 2003; Nelander et al, 2003), requires further investigation (cf Figure 1) Both LIM domain proteins only respond to a particular deforming stimulus, that is, increased stretch due to a rise in circumferential wall tension. That is, the unidirectional dragging force of the flowing blood, to which only EC are subjected, is probably too weak to elicit a translocation of zyxin from FA to the nucleus in EC, while osmotic stress does neither affect the redistribution of LPP nor that of zyxin in vascular SMC
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