Abstract
Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson–Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in LmnaG609G/G609G mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred LmnaLCS/LCSTie2Cre+/tgand LmnaLCS/LCSSM22αCre+/tg mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of LmnaG609G/G609G and LmnaLCS/LCSSM22αCre+/tg, but not in those from LmnaLCS/LCSTie2Cre+/tgmice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, LmnaG609G/G609G arteries exhibit stiffness and inward remodeling, mainly due to progerin‐induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria.
Highlights
Cardiovascular disease (CVD) is the leading cause of death and morbidity worldwide (World Health Organization, 2017)
In addition to the characterization of risk factors epidemiologically associated and contributing to CVD development (D'Agostino et al, 2008), great advances have been made in the definition of tissue and cellular properties underlying age‐induced cardiovascular decline (Lakatta, 2003; Lakatta & Levy, 2003a, 2003b)
2.1 | LmnaG609G/G609G mice ubiquitously expressing progerin show aortic stiffness and inward remodeling that are reproduced in mice with vascular smooth muscle cells (VSMCs)‐specific progerin expression
Summary
Cardiovascular disease (CVD) is the leading cause of death and morbidity worldwide (World Health Organization, 2017). Vessel stiffness is a key player in CVD associated with HGPS, which appears very early and pervasively (Gerhard‐Herman et al, 2012; Gordon et al, 2012), and is an important cardiovascular outcome measure in HGPS clinical trials (Gordon et al, 2012, 2016). Despite the importance of vessel stiffness in the cardiovascular pathophysiology of both HGPS and normal aging, the underlying mechanisms and specific contribution of different cell types have yet to be defined. The present study aims to investigate the mechanisms underlying vessel stiffness in HGPS by analyzing vascular structure and mechanics in mutant LmnaG609G/G609G mice, which express progerin ubiquitously and recapitulate the main clinical manifestations of human HGPS (reduced lifespan, lipodystrophy, and bone and cardiovascular abnormalities; Hamczyk, Villa‐Bellosta et al, 2018; Osorio et al, 2011; Villa‐ Bellosta et al, 2013). We tested the effects of dietary supplementation with sodium nitrite on vascular stiffness in LmnaG609G/G609G mice, a treatment that has been shown to prevent large elastic artery stiffness during normal aging in both mouse and humans, without reported side effects (Rammos et al, 2014; Sindler et al, 2011)
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