Cellular Heterogeneity During Arterial Aging

Aging Cell, vol. 25, pp. e70597

Abstract

Arterial aging is a major risk factor for cardiovascular disease and is associated with progressive changes in vascular structure and function, including arterial stiffening, reduced elasticity, extracellular matrix remodeling, chronic low-grade inflammation, and accumulation of senescence-associated cell states. Recent advances in single-cell RNA sequencing (scRNA-seq) have provided new opportunities to resolve the cellular heterogeneity underlying these age-related alterations in the arterial wall. In this review, we summarize current single-cell studies of arterial aging by focusing first on key phenotypic programs, including cellular senescence, extracellular matrix remodeling, inflammaging, and altered intercellular communication, and then discuss how these programs are reflected in endothelial cells, smooth muscle cells, fibroblasts, and immune cells. Across studies, aging is recurrently associated with endothelial dysfunction, smooth muscle cell phenotypic modulation, fibroblast-related matrix remodeling, and immune activation, although the degree of conservation varies depending on species, vascular bed, sex, and disease context. We further discuss emerging evidence that vascular aging involves not only cell-intrinsic transcriptional changes but also alterations in communication networks across the arterial wall. Although current single-cell studies have substantially improved our understanding of arterial aging, important limitations remain, including inconsistent cell-state annotation across studies, incomplete functional validation, and limited spatial and epigenetic resolution. Future integration of cross-species analyses with spatial transcriptomics, single-cell epigenomic approaches, and functional studies will help refine the cellular framework of arterial aging and improve its translational relevance.

Authors 4

1. He Xu

   Maastricht University

   Affiliation as printed

   Department of Pathology Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Maastricht the Netherlands

2. Paul‐Lennard Mendez

   Max Delbrück Center · Maastricht University · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Berlin Institute of Health at Charité–Universitätsmedizin Berlin Berlin Germany

   Department of Pathology Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Maastricht the Netherlands

   Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB) Berlin Germany

3. Dimitri Kasakovski Aachen Department for Renal and Hypertensive Rheumatological and Immunological Diseases (Medical Clinic II)

   Maastricht University · RWTH Aachen University

   Affiliation as printed

   Department for Renal and Hypertensive Rheumatological and Immunological Diseases (Medical Clinic II), RWTH Aachen Aachen Germany

   Department of Pathology Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Maastricht the Netherlands

4. Judith C. Sluimer Aachen Department for Renal and Hypertensive Rheumatological and Immunological Diseases (Medical Clinic II)

   Maastricht University · British Heart Foundation Centre for Cardiovascular Science · The Queen's Medical Research Institute · RWTH Aachen University · University of Edinburgh

   Affiliation as printed

   British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute The University of Edinburgh Edinburgh UK

   Department for Renal and Hypertensive Rheumatological and Immunological Diseases (Medical Clinic II), RWTH Aachen Aachen Germany

   Department of Pathology Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Maastricht the Netherlands