Oscillatory shear potentiates latent TGF-β1 activation more than steady shear as demonstrated by a novel force generator

Sci Rep. 2019 Apr 15;9(1):6065. doi: 10.1038/s41598-019-42302-x.


Cardiovascular mechanical stresses trigger physiological and pathological cellular reactions including secretion of Transforming Growth Factor β1 ubiquitously in a latent form (LTGF-β1). While complex shear stresses can activate LTGF-β1, the mechanisms underlying LTGF-β1 activation remain unclear. We hypothesized that different types of shear stress differentially activate LTGF-β1. We designed a custom-built cone-and-plate device to generate steady shear (SS) forces, which are physiologic, or oscillatory shear (OSS) forces characteristic of pathologic states, by abruptly changing rotation directions. We then measured LTGF-β1 activation in platelet releasates. We modeled and measured flow profile changes between SS and OSS by computational fluid dynamics (CFD) simulations. We found a spike in shear rate during abrupt changes in rotation direction. OSS activated TGF-β1 levels significantly more than SS at all shear rates. OSS altered oxidation of free thiols to form more high molecular weight protein complex(es) than SS, a potential mechanism of shear-dependent LTGF-β1 activation. Increasing viscosity in platelet releasates produced higher shear stress and higher LTGF-β1 activation. OSS-generated active TGF-β1 stimulated higher pSmad2 signaling and endothelial to mesenchymal transition (EndoMT)-related genes PAI-1, collagen, and periostin expression in endothelial cells. Overall, our data suggest variable TGF-β1 activation and signaling occurs with competing blood flow patterns in the vasculature to generate complex shear stress, which activates higher levels of TGF-β1 to drive vascular remodeling.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Platelets / metabolism
  • Cell Adhesion Molecules / metabolism
  • Collagen / metabolism
  • Computer Simulation
  • Endothelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / physiology
  • Healthy Volunteers
  • Hemodynamics / physiology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Models, Cardiovascular*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Regional Blood Flow / physiology*
  • Signal Transduction / physiology
  • Smad2 Protein / metabolism
  • Stress, Physiological*
  • Transforming Growth Factor beta1 / metabolism*
  • Vascular Remodeling / physiology*


  • Cell Adhesion Molecules
  • POSTN protein, human
  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • SMAD2 protein, human
  • Smad2 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Collagen