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.

Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid Lmna G609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined Lmna LCS/LCS Tie2Cre tg/+ and Lmna LCS/LCS Sm22αCre tg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare genetic disease characterized by accelerated aging and death in adolescence [5][6][7][8][9]. HGPS children have impaired postnatal growth, lipodystrophy, alopecia, pigmented and wrinkled skin, and skeletal dysplasia. They also develop generalized atherosclerosis, arterial stiffness and calcification, electrocardiographic abnormalities, and ventricular diastolic dysfunction and die prematurely at an average age of 14.6 years mainly due to myocardial infarction, stroke, or heart failure [7,10,11]. HGPS is caused by a heterozygous de novo point mutation in the LMNA gene, which encodes the nuclear proteins lamin A and C (A-type lamins) [12,13]. This synonymous mutation activates a cryptic splice donor site that removes 150 nucleotides from exon 11, causing the synthesis of progerin [12,13]. This truncated form of prelamin A is expressed ubiquitously and acts in a dominant-negative manner, causing alterations in many essential nuclear functions, including nuclear structure, gene transcription, signal transduction, DNA damage repair, chromatin organization, mechanosensing, and proliferation [14,15]. Aside from its role in HGPS, progerin is detectable at low levels in several tissues during normal aging, including atherosclerotic coronary arteries, suggesting a role in physiological aging [11,[16][17][18][19].Homozygous Lmna-null mice lacking A-type lamins develop to term without exhibiting overt anomalies, but they develop skeletal muscle dystrophy and dilated cardiomyopathy soon after birth and are all death by the eight week [20]. Interest...

Background: Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly due to myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. Methods: We used CRISPR/Cas9 technology to generate Lmna HGPSrev/HGPSrev (HGPSrev) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell-type-specific manner upon Cre recombinase activation. We characterized the phenotype of HGPSrev mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells (VSMCs) and cardiomyocytes. Results: Like HGPS patients, HGPSrev mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, VSMC loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, p<0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon early intervention (84.5% lifespan extension in mildly symptomatic mice, p<0.0001, and 6.7% in severely ill mice, p<0.01). Remarkably, major vascular alterations were prevented and lifespan normalized in HGPSrev mice when progerin suppression and lamin A restoration were restricted to VSMCs and cardiomyocytes. Conclusions: HGPSrev mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to VSMCs and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan.

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