Smooth Muscle Cell Death Drives an Osteochondrogenic Phenotype and Severe Proximal Vascular Disease in Progeria.
Sae-Il MurtadaYuki KawamuraCristina CavinatoMo WangAbhay B RamachandraBart SpronckGeorge TellidesJay D HumphreyPublished in: bioRxiv : the preprint server for biology (2023)
Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end of life. We associate progressive deterioration of arterial structure and function with single cell transcriptional changes, which reveals a rapid disease process in proximal elastic arteries that largely spares distal muscular arteries. These data suggest a novel sequence of progressive vascular disease in progeria: initial extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death in proximal arteries, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotypic modulation that results in an accumulation of proteoglycans that thickens the wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased pulse wave velocity drives left ventricular diastolic dysfunction, the primary diagnosis in progeria children. Mitigating smooth muscle cell loss / phenotypic modulation promises to have important cardiovascular implications in progeria patients.
Keyphrases
- smooth muscle
- cell death
- stress induced
- single cell
- left ventricular
- extracellular matrix
- blood pressure
- blood flow
- ejection fraction
- multiple sclerosis
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- rna seq
- prognostic factors
- oxidative stress
- young adults
- gene expression
- stem cells
- patient reported outcomes
- aortic stenosis
- acute myocardial infarction
- peritoneal dialysis
- high throughput
- body composition
- mitral valve
- coronary artery disease
- acute coronary syndrome
- hypertrophic cardiomyopathy
- signaling pathway
- drug induced
- case report
- left atrial
- big data
- cardiac resynchronization therapy