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Related Experiment Video

Updated: Aug 16, 2025

The Assembly and Application of 'Shear Rings': A Novel Endothelial Model for Orbital, Unidirectional and Periodic Fluid Flow and Shear Stress
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Shear-mediated ALK5 expression regulates endothelial activation.

Kuin Tian Pang1, Mean Ghim1, Padmini Sarathchandra2

  • 1Department of Bioengineering, Imperial College London, United Kingdom.

Biochemical and Biophysical Research Communications
|December 25, 2022
PubMed
Summary
This summary is machine-generated.

Transforming growth factor-β (TGF-β) receptor ALK5 plays a key role in calcific aortic valve disease. Disturbed blood flow alters ALK5 signaling, increasing inflammation and valve permeability, suggesting ALK5 as a therapeutic target.

Keywords:
Cardiovascular diseaseEndothelial cellsEndothelial-to-mesenchymal transitionMechanosensingMonocyte adhesionParacellular transportShear stressSignal transductionTGF-β

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Area of Science:

  • Cardiovascular Biology
  • Mechanobiology
  • Endothelial Cell Biology

Background:

  • Calcific aortic valve disease (CAVD) preferentially affects the aortic side of the valve due to disturbed blood flow.
  • Endothelial dysfunction and inflammation precede overt CAVD.
  • The transforming growth factor-β (TGF-β) receptor ALK5 is a known mechanosensor, but its role in flow-induced valve pathology is unclear.

Purpose of the Study:

  • To investigate the role of ALK5 in flow-induced endothelial dysfunction and inflammation relevant to CAVD.
  • To elucidate the mechanism by which ALK5 signaling mediates responses to disturbed blood flow.

Main Methods:

  • Utilized human umbilical vein endothelial cell (HUVEC) monolayers subjected to low magnitude multidirectional flow.
  • Assessed ALK5 receptor expression, SMAD2/3 phosphorylation, monocyte adhesion, and transendothelial albumin transport.
  • Inhibited ALK5 kinase activity to determine its functional role.
  • Examined ALK5 expression in porcine aortic valve tissue.

Main Results:

  • Low magnitude multidirectional flow downregulated ALK5 and increased SMAD2 phosphorylation in HUVECs.
  • These changes correlated with increased monocyte adhesion and albumin transport across the endothelial barrier.
  • Inhibition of ALK5 kinase activity abolished these flow-induced pathological effects.
  • In vivo analysis of porcine aortic valves supported the in vitro findings.

Conclusions:

  • ALK5 mechanosensory signaling is critical in mediating endothelial responses to disturbed blood flow.
  • Dysregulated ALK5 signaling contributes to inflammation and increased permeability in the context of CAVD.
  • Targeting ALK5 may offer a novel therapeutic strategy for shear stress-associated cardiovascular diseases like CAVD.