Advanced science (Weinheim, Baden-Wurttemberg, Germany)Jul 2, 2026

Stiffer Surroundings May Cause Aging in Blood Vessel Cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 3, 2026

Abstract

Increased mechanical stress from extracellular matrix (ECM) stiffening induces an endothelial cell senescence phenotype characterized by elevated p16/p21 levels.

Matrix stiffening leads to an endothelial cell senescence phenotype without inflammatory signals.
Elevated levels of p16/p21 and a senescence-associated secretory phenotype (SASP) are observed in response to ECM stiffening.
Activation of Notch signaling is associated with mechano-induced senescence.
Treatment with an FDA-approved γ-secretase inhibitor reduces stiffness-induced senescence.
Analysis of fibrotic tissue from patients reveals an increase in p16+Notch1+ endothelial cells.

Simplified

Identifying the drivers of cellular senescence that contribute to the decline in vascular function with age and disease is critical for developing restorative interventions. Here, we investigated how increased mechanical stress from extracellular matrix (ECM) stiffening shapes endothelial cell (EC) senescence. We developed a 3D human in vitro model that decouples mechanical stress from inflammatory or biochemical signals, enabling the study of senescence responses to tissue stiffening alone. We found that matrix stiffening induces an EC senescence phenotype with elevated p16/p21 and an immunomodulatory senescence-associated secretory phenotype (SASP), in the absence of inflammatory signals. This mechano-induced senescence activates Notch signaling, and treatment with an FDA-approved γ-secretase inhibitor attenuates stiffness-induced senescence. Analysis of fibrotic capsule tissue from patients with synthetic breast implants, a model of localized, mechanically driven fibrosis, validated an increase in p16⁺Notch1⁺ endothelial populations. Complementary single-cell RNA sequencing data further confirmed enrichment of Notch- and SASP-related gene programs. Our work provides a human-relevant platform for studying targetable stages of endothelial mechanoaging and identifies potential therapeutic targets associated with stiffness-induced endothelial senescence for mechanically remodeled tissues.