Role of the focal adhesion protein zyxin in hypertension-induced cardiovascular remodelling

Abstract

Hypertension is one of the leading causes of morbidity and mortality worldwide, serving as a major risk factor for cardiovascular events such as stroke, myocardial infarction and diabetes. Although clinically well studied, relatively little is known about the cellular mechanisms at the onset of this disease. A chronic increase in arterial wall tension in hypertension translates into elevated levels of biomechanical stretch experienced by vascular smooth muscle cells (SMCs). This leads to prominent changes in gene expression initiating a complex remodelling process driven by a shift in phenotype of otherwise contractile vascular SMCs to an activated, synthetic state. Therefore, mechanotransduction in vascular SMCs in response to altered hemodynamic forces is a crucial step in the progression of hypertension-induced maladaptive remodelling. In this context, we and others have identified the focal adhesion protein zyxin as a putative mechanotransducer which regulates the cellular adaptation to exaggerated biomechanical stretch. As such, we hypothesized that zyxin might play an important role in hypertension-induced cardiovascular remodelling. This work addressed the functional consequences of loss of zyxin during pathological remodelling of arteries and the heart in hypertensive mice. Microarray analysis revealed a dramatic alteration of stretch-regulated gene expression in zyxin-null vascular SMCs. A comparison of vascular SMCs from wild type and zyxin-null mice revealed a growth-promoting, pro-migratory, anti-apoptotic and poorly contractile phenotype of zyxin-null vascular SMCs. This could be attributed to an activation of the RhoA-MRTF-A signalling axis partially driving stretch-induced gene expression in the zyxin-null SMCs. Induction of experimental hypertension led to a significantly lower increase in systolic and diastolic arterial blood pressure in zyxin-null mice particularly in older animals, an outcome that could be attributed to structural changes in the remodelling arteries. This response was paralleled by a reduced resistivity in the femoral artery of these animals likely caused by a loss of extracellular matrix (ECM) integrity observed in older zyxin-null mice. Hemodynamic overload further induced pronounced cardiac interstitial fibrosis, apoptosis and resultant cardiac dysfunction in zyxin-null mice, owing to a major shift towards a pro-fibrotic gene expression pattern within the myocardium, most likely derived from the cardiac fibroblasts. Lastly, using a ratiometric calcium imaging method, this study confirmed a TRPC3 channel-dependent stretch-induced zyxin activation in vascular cells that is mediated through activation of the beta 1 isoform of phospholipase C. Collectively, these findings highlight a novel role of zyxin in hypertension-induced cardiovascular remodelling and underscore the importance of mechanotransduction in the pathophysiology of this highly prevalent cardiovascular disease.