Abstract 10730: Vascular Smooth Muscle Cell Phenotypic Switch and Replication Stress as a Key Contributors in CVD in HGPS

Abstract

Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Patients show severe aging phenotypes, including alopecia, reduced fat and bone density, and cardiovascular disease (CVD), which ultimately causes their death as teenagers. HGPS has no cure and clinical trials obtained only minor benefits. It is urgent to identify mechanisms of progerin toxicity to target therapeutically. Progerin accumulates preferentially in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening and aortic atherosclerosis are accompanied by VSMCs depletion in the media, increased extracellular matrix (ECM), and adventitia thickening. Mechanisms whereby progerin causes massive VSMC loss and ECM accumulation are unknown. We previously demonstrated that progerin expression in fibroblasts hinders DNA replication, causes genomic instability, and triggers a phenotypic switch towards activated fibroblasts/myofibroblasts. These cells are known to promote tissue fibrosis by ECM deposition and release of inflammatory cytokines. VSMCs can also undergo phenotypic modulation or de-differentiation, a process whereby contractile cells revert to a synthetic/proliferative phenotype, leading to pathological accumulation of ECM and CVD. Here we show that progerin expression in VSMCs causes a switch towards the synthetic/proliferative phenotype. Similarly to fibroblasts, progerin represents a challenge for DNA replication in VSMC, triggering replication stress, genomic instability and ultimately VSMC death. Importantly, we found that calcitriol -hormonal active form of vitamin D- prevents VSMC switch and replication stress. Our data suggest that replication stress might be an underlying cause of VSMC loss in progeria and that preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might prevent the massive loss of VSMC and the vascular stiffness in HGPS patients.