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Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
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Related Experiment Video

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Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway.

Eri Matsuo1, Takayuki Okamoto2, Atsushi Ito3

  • 1Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie, 514-8507, Japan.

Experimental Cell Research
|September 20, 2021
PubMed
Summary

Endothelial cells sense substrate stiffness, altering YAP-Dll4-Notch signaling. This mechanotransduction regulates cell function, impacting vascular structure and angiogenesis.

Keywords:
Dll4Endothelial cellsNotch-1Substrate stiffnessYAP

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Area of Science:

  • Cell Biology
  • Biophysics
  • Vascular Biology

Background:

  • Endothelial cells maintain vascular integrity by sensing extracellular substrate stiffness.
  • Substrate stiffness influences endothelial cell mechano-transduction via yes-associated protein 1 (YAP) activation.
  • Delta-like ligand 4 (Dll4)-Notch1 signaling is crucial for angiogenesis.

Purpose of the Study:

  • To investigate the impact of substrate stiffness on the interrelation between YAP and Dll4-Notch1 signaling in endothelial cells.
  • To elucidate how these pathways dictate endothelial cell functions in response to mechanical cues.

Main Methods:

  • Culturing endothelial cells on substrates of varying stiffness.
  • Quantifying cellular morphology, YAP activation, and gene expression (Dll4, Notch1, VEGFRs, inflammatory markers, coagulation factors).
  • Utilizing YAP signaling inhibition to confirm its role in observed responses.

Main Results:

  • Endothelial cells on softer substrates showed elongated morphology and attenuated YAP activation compared to stiffer substrates.
  • Softer substrates led to increased Dll4 expression via YAP signaling, alongside VEGFR upregulation.
  • Gene expression changes included suppressed pro-inflammatory markers (IL-6, PAI-1) and modulated expression of anti-coagulant (thrombomodulin) and pro-coagulant (tissue factor) genes.

Conclusions:

  • Endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness.
  • This mechanotransduction pathway modulates endothelial cell functions, including angiogenesis, inflammation, and coagulation.
  • Substrate stiffness is a critical regulator of endothelial cell behavior through YAP-Dll4-Notch signaling.