Multiple signaling pathways in flow-mediated endothelial mechanotransduction: PYK-ing the right location.

The endothelial monolayer is a signal transduction interface for blood-borne mechanical as well as chemical stimuli. The structural deformation arising from a mechanical stimulus, such as a change of hemodynamic shear stress, is conceptually different from the binding of a hormone or other agonist to its specific receptor, yet both elicit important endothelial signaling responses. Mechanical and chemical signaling appear to use common as well as unique pathways downstream of the initial stimulus. For example, signaling pathways arising from membrane deformation and hormone-receptor coupling may appear to converge through activation of phospholipases1 or nuclear factor B transcription factor complex2 but later diverge at the level of DNA binding3 (Figure 1). However, simple interpretations of mechanotransduction are confounded by intracellular and pericellular force transfer, principally by the cytoskeleton,4,5 that results in the generation of transduction pathways at multiple sites throughout the cell, ie, decentralized mechanotransduction.6,7 Thus, although flow-induced shear stress acts at the luminal surface of the endothelial monolayer, the forces are transmitted to cell junctions, nuclear structures, basal adhesion sites, and organelles that are structurally interconnected. This spatial organization of intracellular signaling may result in the stimulation of multiple parallel, convergent, and/or divergent mechanotransduction pathways. The mechanism of transduction of a purely mechanical signal to second messenger pathways such as IP3-driven intracellular calcium mobilization8 or mitogen-activated protein kinases (MAPK) activation9 is unknown. Major efforts are therefore underway to understand endothelial mechanotransduction in terms of the initial stimulus, the generation of second messengers, the activation of transcription factors, and altered gene and protein expression that lead to structural and functional consequences. Recently, the spatial elements of mechanotransduction are receiving attention, in part because of recognition of structural continuity in the distribution of cellular strain,5 and an appreciation of the 3-dimensional dynamics of signaling pathways. A new study reported in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology10 identifies for the first time a role for the spatially versatile protein-rich tyrosine kinase, PYK2, in shear stress mechanotransduction.