The unfolded protein response in progeria arteries originates from non-endothelial cell types.

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease caused by a mutation in LMNA, leading to the expression of a prelamin A variant called progerin. HGPS hallmarks include accelerated cardiovascular disease and atherosclerosis, caused in part by ER stress-induced apoptosis of vascular smooth muscle cells. As a dysregulated unfolded protein response (UPR) can induce endothelial cell (EC) pathology during aging, we investigated whether loss of proteostasis contributes to EC dysfunction in HGPS, using an endothelium-specific HGPS mouse model. Contrary to previous reports in vascular smooth muscle cells and fibroblasts, we found no robust activation of UPR in ECs constitutively expressing progerin, and cells retained the ability to elicit potent UPR when exposed to external ER stress. Unlike aortic tissue derived from mice with endothelium-specific progerin expression, aorta from Lmna ^G609G/+ mice with ubiquitous progerin expression showed up-regulation of the UPR, suggesting that the UPR in HGPS aorta is primarily rooted in non-ECs. Analysis of scRNA-Seq datasets from aorta in Lmna ^G609G/G609G mice confirmed this hypothesis. Our data indicate that UPR activation is a cell-type-specific phenomenon in progerin-expressing arteries.