It is important to say that product keys are required for activation of AutoDesk products and are used to differentiate products that are sold independently and as part of a set of products.
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X-force CFD 2005 Activation
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.
In this study, we programmed a cone-and-plate device to generate a spike in shear rate change during OSS by abruptly switching the cone rotation and modeled the change in shear rate by computational fluid dynamics (CFD) simulation to compare platelet-derived LTGF-β1 activation and its signaling responses in endothelial cells.
Our study shows that OSS generates biologically-active TGF-β1 at a significantly higher rate than SS. To delineate if OSS could lead to higher TGF-β1 activation than SS, we designed a cone-and-plate device that utilized precise control of rotation to generate a spike in shear stress during OSS, which resulted in higher LTGF-β1 activation than SS. One advantage of our device, which can generate both SS and OSS, is that it uses the same settings in the same and different samples to avoid inter- and intra-assay variables. This system has another advantage in that it can be incorporated in a 96-well manifold, enabling high-throughput screening of inhibitors/activators of sheared sensor molecule targets, such as LTGF-β116,18,20 and von Willibrand factor (vWf)21. Thus, these modifications could prove advantageous for drug development for diseases involving high and complex shear, such as atherosclerosis22, aortic stenosis6, or lymphedema23, where changes in shear stress occur.
The higher molecular strain due to the change of shear rate during the abrupt switch of cone rotation (tangential interludes) highlights a critical factor for higher LTGF-β1 activation. However, the mechanism through which shear activates TGF-β1 requires further study to identify specific molecular shear sensor regions, such as the vWf A2 domain24. The crystal structure of TGF-β1 suggests it may be too small to sense shear, but whole latent complex with LTBP-1 structure may provide insight into these activation mechanisms25. We previously demonstrated that LTBP-1 in the latent complex is required for shear-dependent LTGF-β1 activation16. Our previous study also showed thiol disulfide exchange contributes to shear-dependent LTGF-β1activation. Our data indicates that OSS induces higher thiol oxidation and disulfide-bonded HMW complex(es) accumulation, confirming our previous implication that thiol disulfide exchanges contribute to shear-dependent LTGF-β1 activation16,18,26. It is possible that the LTGF-β1 is associated with disulfide-bonded complex(es) that is much larger than proteins like vWf, which can itself be sensed by shear. Future study is needed to elucidate additional mechanistic insight for LTGF-β1 activation by SS vs. OSS via thiol disulfide exchange mechanism.
We recently showed that shear-activated platelet TGF-β1 directly contributes to aortic stenosis (AS) progression in a robust mouse model19. EndoMT is a phenomenon induced by TGF-β1 signaling17, and we found platelets are physically attached with valvular endothelial cells inducing mesenchymal transition19. These results suggest further studies should determine whether OSS-induced TGF-β1 activation around valve leaflets contributes to AS progression. Our data shows that platelet releasates subjected to OSS can induce TGF-β signaling in endothelial cells for p-Smad2 and genes responsible for the EndoMT process, a hallmark of pathologic organ fibrosis28. These findings suggest that areas where OSS is generated, such as in aortic stenosis, are more likely to display EndoMT, a hallmark of atherosclerosis29 and fibrosis17.
Our data also suggest increased TGF-β1 activation in OSS may have clinical implication related to hemodynamic changes seen during atherosclerotic plaque rupture and subsequent thrombosis in myocardial infarctions, where high shear (turbulent/oscillatory) is generated by tissue factor-mediated thrombus formation and platelet activation inside the closing vessels2,4. During this event, platelet TGF-β1 activation may substantially induce signaling for fibrosis development later in life. Our study shows that higher TGF-β1 activation by OSS leads to increased TGF-β1 signaling as measured by p-Smad2, PAI-1, and collagen synthesis. These findings are consistent with a recent report showing that oscillatory shear exposure induces collagen deposition in fibrotic aortic valves30. We also posit that areas in which oscillatory shear occurs, such as AS and/or atherosclerotic plaques, may predict a deleterious outcome for fibrosis or plaque ruptures1,31. Thus, our results have pathological implications in vivo where similar measurements can calculate the effects of different forms of shear changes, such as remodeling during wound healing or pathological remodeling in fibrosis. Studies using in vivo animal models will validate this hypothesis. 2ff7e9595c
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