Oscillatory shear potentiates latent TGF-?1 activation more than steady shear as demonstrated by a novel force generator.

ABSTRACT: Cardiovascular mechanical stresses trigger physiological and pathological cellular reactions including secretion of Transforming Growth Factor ?1 ubiquitously in a latent form (LTGF-?1). While complex shear stresses can activate LTGF-?1, the mechanisms underlying LTGF-?1 activation remain unclear. We hypothesized that different types of shear stress differentially activate LTGF-?1. 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-?1 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-?1 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-?1 activation. Increasing viscosity in platelet releasates produced higher shear stress and higher LTGF-?1 activation. OSS-generated active TGF-?1 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-?1 activation and signaling occurs with competing blood flow patterns in the vasculature to generate complex shear stress, which activates higher levels of TGF-?1 to drive vascular remodeling.

SUBMITTER: Kouzbari K 

PROVIDER: S-EPMC6465594 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature