In the aortas of mice with progeria, stress in the cellular compartment responsible for protein folding precedes smooth muscle cell state changes, cell death, and mutation accumulation

In the aortas of mice with progeria, stress in the cellular compartment responsible for protein folding precedes smooth muscle cell state changes, cell death, and mutation accumulation

On July 31, Genome Medicine published a cellular map of the aortic arch in mice carrying a mutation that models the most common form of human progeria. The map traces the sequence of changes specifically in the smooth muscle cells of the vascular wall.

In Hutchinson-Gilford progeria syndrome, a mutation in the LMNA gene causes cells to produce progerin, an altered form of a nuclear envelope protein. In children with this syndrome, arteries rapidly lose their normal structure, and cardiovascular complications become the leading cause of death.

Smooth muscle cells form the middle layer of the artery. They contract and help the vessel withstand each pulse of blood. In this study, the authors examined 8 968 cells from the aortic arches of mice aged 6, 10, and 12 weeks.

At six weeks, some smooth muscle cells had already activated the endoplasmic reticulum stress response. The endoplasmic reticulum is the cellular compartment where proteins acquire their shape. By ten weeks, the cells showed lower expression of genes required for contraction and higher expression of genes associated with fibroblasts, which are connective tissue cells. Cell loss in the muscular layer of the aorta began at seven weeks. Later, the apoptotic program responsible for controlled cell death became more active.

By twelve weeks, these same cells had accumulated more DNA damage and somatic single-nucleotide variants, which are substitutions of individual DNA letters that arise in cells of the body. The increase in variant number correlated with the activity of genes involved in endoplasmic reticulum stress, the oxidative stress response, and p53. Fibroblasts accumulated these variants later.

In this mouse model, endoplasmic reticulum stress is detectable in smooth muscle cells before they change state and begin to die in large numbers. Earlier evidence had also linked this stress response to vascular disease in progeria. In a 2019 study, chemically suppressing this pathway in mice slowed cell loss. The new time series identifies the period during which smooth muscle cells still retain features of their usual contractile role.