Dietary Restriction Mitigates Vascular Aging, Modulates the cGAS-STING Pathway and Reverses Macrophage-Like VSMC Phenotypes in Progeroid DNA-Repair-Deficient Ercc1^Δ/- Mice

Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1 Δ/− mice and to explore the therapeutic effect of dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression of vascular aging processes, including extracellular matrix remodeling, in the Ercc1 Δ/− aorta. Notably, this analysis indicated the presence of macrophage-like vascular smooth muscle cells (VSMCs) and suggested cGAS-STING pathway activation. The presence of macrophage-like VSMCs and increased STING1 expression were confirmed in Ercc1 Δ/− aortic tissue and were both reduced by DR. In vitro, cisplatin-induced DNA damage activated the cGAS-STING pathway in Ercc1 Δ/− VSMCs but not in wildtype VSMCs. These findings identify the involvement of the cGAS-STING pathway in DNA damage-driven vascular aging and underscore the therapeutic benefits of DR for vascular aging. Furthermore, upstream regulator analysis revealed compounds that may replicate the beneficial effects of DR, providing promising leads for further investigation.</p

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation

RationalePathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis.ObjectivesInvestigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants.MethodsA retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts.ResultsIndividuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0–47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0–54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines.ConclusionDistinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs