Single-Cell Analysis Reveals Transcriptomic Reprogramming in Aging Cardiovascular Endothelial Cells

Abstract

The senescence of cardiovascular endothelial cells (ECs) is a major risk factor in the development of aging-related cardiovascular diseases. However, the molecular dynamics in cardiovascular EC aging are poorly understood. Here, we characterized the transcriptomic landscape of cardiovascular ECs during aging and observed that ribosome biogenesis, inflammation, apoptosis and angiogenesis-related genes and pathways changed with age. We also highlighted the importance of collagen genes in the crosstalk between ECs and other cell types in cardiovascular aging. Moreover, transcriptional regulatory network analysis revealed Jun as a candidate transcription factor involved in murine cardiovascular senescence and we validated the upregulation of Jun in aged cardiovascular ECs both in vitro and in vivo. Altogether, our study reveals the transcriptomic reprogramming in the aging murine cardiovascular ECs, which deepens the understanding of the molecular mechanisms of cardiovascular aging and provides new insights into potential therapeutic targets against age-related cardiovascular diseases.

Targeting the redox system for cardiovascular regeneration in aging

“…The cardiovascular system is principally vulnerable to ROS‐induced oxidative damage due to its high metabolic demand and low antioxidant defense capacity in aging (Sorrentino et al., 2019 ; Xie et al., 2023 ). Accordingly, single‐cell RNA‐Seq analysis of mouse aged cardiovascular ECs reveals transcriptomic reprogramming, including upregulation of reactive oxygen species metabolic process in these cells (Gou et al., 2022 ). In Macaca fascicularis monkeys, scRNA‐seq of aortas also shows an inactivation of forkhead box O3A (FOXO3A) in arterial ECs that recapitulates the major phenotypic defects observed in aged monkey aortas.…”

Mass Spectrometry-based Profiling of Single-cell Histone Post-translational Modifications to Dissect Chromatin Heterogeneity

“…1C). Notably, we achieved comprehensive coverage of the N-terminal tails of H3 and H4, in particular of peptides H3 (9)(10)(11)(12)(13)(14)(15)(16)(17) and H4(4-17) that were identified with multiple peptidoforms, demonstrating the sensitivity of our method. Missing regions included the H2B N-terminus and H1 C-terminus that lack arginine residues, resulting in long and hydrophobic peptides.…”

“…For the H4 N-terminal peptide H4 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), encompassing four modifiable lysines, several isobaric forms were detected in different degrees of acetylation that are often co-eluting. Therefore, a combination of unique fragments were used for identification of these peptidoforms (Supplementary Fig.…”

“…Additionally, established singlecell sequencing methods, such as single-cell RNA-sequencing, have showcased that conventional analyses of large cell populations mask the inherent cell-to-cell variability, therefore limiting the ability to uncover subtle differences that may drive disease progression 13 . Single-cell analysis enables the identification of rare cell subpopulations, thereby offering insights into cellular heterogeneity, transitions, and responses to stimuli, which has shown significant relevance in cancer and aging research [14][15][16][17] . For example, in the context of cancer, single-cell resolution is essential for precisely identifying therapy-resistant subpopulations that may emerge and lead to minimal residual disease 18 .…”

Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases

“…The GO enrichment revealed that ribosome biogenesis-related pathways were enriched in EC-4 (Figure S2D), suggesting a relatively more mature state of these cells 64 or an aging endothelial phenotype. 65 These data suggested that heterogeneous populations of aortic ECs may perform distinct physiological functions.…”