Vascular Disease in Hutchinson Gilford Progeria Syndrome and Aging: Common Phenotypes and Potential Mechanisms

Hutchinson Gilford progeria syndrome (progeria) is a rare childhood segmental progeroid syndrome which shares similarities with the pathology of vascular disease of normal aging adults, making it an attractive model to study the development of vascular disease on an accelerated timescale. Clinical evaluations of children with progeria and histological analyses of vascular autopsy specimens have yielded compelling evidence to suggest that vascular disease in progeria is highly similar to progressive atherosclerosis seen in aging adults. However, lesion development is very rapid and advanced, including severe stenosis with abundant fibrotic extracellular matrix, smaller necrotic cores and a paucity of lipid accumulation. Additionally, children with progeria do not experience an increase in vascular intimal-medial thickness often seen in adult cardiovascular disease, and display extensive adventitial fibrosis throughout the vasculature. Unlike other progeroid laminopathies, mutations in the LMNA gene that lead to the production of progerin appear to be necessary for the manifestation of atherosclerosis. Mounting evidence of low-level progerin expression in normal aging vascular tissues suggests that progerin may act as a common mechanism driving the development of atherosclerosis in progeria and aging. Through alterations in chromatin organization and transcription factor expression, progerin impacts extracellular matrix expression in a way that potentially promotes lipid retention, inflammation, and altered mechanical signaling to induce vascular stiffening, hypertension, and accelerated atherosclerosis. Additionally, by promoting persistence of DNA damage, telomere attrition, and vulnerability to stress, progerin induces vascular cell senescence and reduced viability which independently contributes to the progression of vascular disease. Several mouse models of progeria are now being used to test potential therapies, some of which have progressed to clinical trials, providing children with progeria the first real hope in fighting the disease.