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Related Experiment Video

Updated: Jul 3, 2026

Measuring the Stiffness of Ex Vivo Mouse Aortas Using Atomic Force Microscopy
10:35

Measuring the Stiffness of Ex Vivo Mouse Aortas Using Atomic Force Microscopy

Published on: October 19, 2016

Matrix Stiffness Induces Endothelial Network Senescence.

Jiyeon Song1, Alexandra N Rindone2, Ya Guan1

  • 1Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 2, 2026
PubMed
Summary
This summary is machine-generated.

Tissue stiffening drives endothelial cell senescence, a key factor in vascular aging. This study reveals that targeting Notch signaling can reverse this process, offering new therapeutic avenues for age-related vascular decline.

Keywords:
biomaterialcell biologyendothelial stem cellengineered tissueextracellular matrixfibrosishydrogel scaffoldnotch signaling pathwayphenotypesenescence

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Last Updated: Jul 3, 2026

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10:35

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Published on: October 19, 2016

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Published on: July 5, 2018

Area of Science:

  • Vascular Biology
  • Cellular Aging
  • Biomaterials Science

Background:

  • Cellular senescence contributes to age-related vascular dysfunction.
  • The role of mechanical stress, specifically extracellular matrix (ECM) stiffening, in endothelial cell (EC) senescence is not fully understood.
  • Existing models often confound mechanical stress with inflammatory or biochemical factors.

Purpose of the Study:

  • To investigate how increased mechanical stress from ECM stiffening induces endothelial cell senescence.
  • To develop and utilize a 3D human in vitro model that isolates mechanical stress effects.
  • To identify potential therapeutic targets for stiffness-induced endothelial senescence.

Main Methods:

  • Developed a 3D human in vitro model to decouple mechanical stress from other signals.
  • Assessed senescence markers (p16/p21) and senescence-associated secretory phenotype (SASP) in ECs under varying matrix stiffness.
  • Utilized Notch signaling pathway inhibitors and analyzed patient-derived fibrotic tissues.
  • Performed single-cell RNA sequencing to analyze gene expression profiles.

Main Results:

  • Matrix stiffening alone induced an endothelial cell senescence phenotype, characterized by elevated p16/p21 and SASP.
  • Mechano-induced senescence activated Notch signaling.
  • Treatment with a γ-secretase inhibitor attenuated stiffness-induced senescence.
  • Patient fibrotic tissues showed increased populations of p16+/Notch1+ endothelial cells, validating the in vitro findings.
  • Single-cell RNA sequencing confirmed enrichment of Notch and SASP-related gene programs.

Conclusions:

  • ECM stiffening is a direct driver of endothelial cell senescence, independent of inflammation.
  • The Notch signaling pathway is a critical mediator of stiffness-induced endothelial senescence.
  • This study provides a human-relevant model for studying endothelial mechanoaging and identifies Notch signaling as a potential therapeutic target for mechanically remodeled tissues.