Fluid shear stress-mediated signal transduction: how do endothelial cells transduce mechanical force into biological...

We propose a model for signaling events induced by fluid shear stress that incorporates many of the features discussed in this paper (FIG. 4). First, heterotrimeric G-proteins, as well as a small G-proteins, are activated by flow. Indeed, a G protein appears to be required for ERK1/2 activation by flow because ERK1/2 activation is completely inhibited by GDP-beta S. Then, flow activates phospholipase C and generates IP3 and diacylglycerol (DG). IP3 releases Ca2+ from internal Ca2+ stores via IP3 receptor and DG activates PKC. Nollert and colleagues have shown that flow activates PLC and increases IP3. It is possible that several different PKC isozymes are activated by flow including both Ca(2+)-dependent and Ca(2+)-independent isozymes. These different isozymes may have specific downstream substrates. For example, PKC-epsilon may be involved in activation of ERK1/2, while the PKC isozyme responsible for activation of JNK remains unknown. It is also possible that these PKC isozymes may be important in gene transcription events. For example, PKC-zeta has been suggested to be involved in NF-kappa B-mediated gene transcription. Longer term changes in endothelial cell morphology and structure are likely to involve separate kinases. Important candidates for these changes include members of the c-Src and FAK families. c-Src is now considered to be a component of the focal adhesion complex and regulate focal adhesion formation and/or cytoskeletal rearrangement. Recently, stretch, another mechanostress, has been shown to activate c-Src in fetal rat lung cells. It has been clarified that ERK1/2 and JNK are regulated by the small G-proteins, Ras and Rac/Cdc42H, respectively, and their effectors in parallel with each other. Rac and Rho are also thought to be involved in membrane ruffling and/or cytoskeletal rearrangement. Fluid shear stress causes stress fiber formation and focal adhesion rearrangement. Recent study by Malek and Izumo suggested the importance of microtubules in shear stress-induced morphological change and actin stress fiber formation. It is clear that the focal adhesion complex plays an important role in shear stress-induced signal and it is interesting to speculate that shear stress-induced signaling has cross-talk with signaling induced by integrins. As a general model we propose that the integration between the rapid events stimulated by shear stress and the longer term events is mediated by tyrosine kinases that serve to regulate these multiple signal transduction pathways.