Mechanotransduction of the vasculature in Hutchinson-Gilford Progeria Syndrome

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder that causes severe cardiovascular disease, resulting in the death of patients in their teenage years. The disease pathology is caused by the accumulation of progerin, a mutated form of the nuclear lamina protein, lamin A. Progerin binds to the inner nuclear membrane, disrupting nuclear integrity, and causes severe nuclear abnormalities and changes in gene expression. This results in increased cellular inflammation, senescence, and overall dysfunction. The molecular mechanisms by which progerin induces the disease pathology are not fully understood. Progerin's detrimental impact on nuclear mechanics and the role of the nucleus as a mechanosensor suggests dysfunctional mechanotransduction could play a role in HGPS. This is especially relevant in cells exposed to dynamic, continuous mechanical stimuli, like those of the vasculature. The endothelial (ECs) and smooth muscle cells (SMCs) within arteries rely on physical forces produced by blood flow to maintain function and homeostasis. Certain regions within arteries produce disturbed flow, leading to an impaired transduction of mechanical signals, and a reduction in cellular function, which also occurs in HGPS. In this review, we discuss the mechanics of nuclear mechanotransduction, how this is disrupted in HGPS, and what effect this has on cell health and function. We also address healthy responses of ECs and SMCs to physiological mechanical stimuli and how these responses are impaired by progerin accumulation.

Keywords: atherosclerosis; endothelial cell; lamin a; mechanotransduction; progeria; progerin; vascular smooth muscle cell.

FIGURE 1

Schematic illustrating the primary mechanosensing elements of ECs including G-protein coupled receptors (GPCRs), adhesion molecules, ion channels, receptor tyrosine kinases, integrins, caveolae, and the glycocalyx. Also depicted are the components of the LINC complex. Lamins and, in the case of HGPS, progerin, are localized to the nuclear periphery and bind DNA or transcription factors. SUN proteins bridge the nuclear membrane, connecting intranuclear lamins with extranuclear KASH proteins (nesprins 1-4). These nesprins then bind to the cytoskeletal elements actin, microtubules, and intermediate filaments that are connected to or influenced by the various mechanosensors. Thus, the complete mechanotransductive pathway that regulates gene expression in response to external mechanical stresses can be visualized. This figure was generated using BioRender.

FIGURE 2

Schematic depicting several mechanisms that are involved in the significant SMC loss seen in HGPS, including elevated matrix metalloproteinase 13 (MMP13) secretion and endoplasmic reticulum (ER) stress, reduced vimentin and poly [ADP-ribose] polymerase 1 (PARP1) expression, and decreased levels of lamin B. Lower lamin B in concert with progerin accumulation increases nuclear stiffness, leading to greater incidence of nuclear rupture and DNA damage that ultimately results in increased SMC apoptosis. This figure was generated using BioRender.