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...