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
- left ventricular
- single cell
- stress induced
- extracellular matrix
- blood pressure
- blood flow
- end stage renal disease
- ejection fraction
- multiple sclerosis
- chronic kidney disease
- heart failure
- early onset
- rna seq
- newly diagnosed
- young adults
- oxidative stress
- stem cells
- high throughput
- minimally invasive
- transcription factor
- patient reported outcomes
- prognostic factors
- cell therapy
- left atrial
- electronic health record
- quantum dots
- bone marrow
- big data
- drug induced
- amino acid
- sensitive detection