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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1755.)
© 2002 American Heart Association, Inc.

Editorials

Multiple Signaling Pathways in Flow-Mediated Endothelial Mechanotransduction

PYK-ing the Right Location

Peter F. Davies

From the Institute for Medicine and Engineering, and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.

Correspondence to Dr Peter F. Davies, Director, Institute for Medicine and Engineering, University of Pennsylvania, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA 19104-6383. E-mail pdf@pobox.upenn.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

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, . . . [Full Text of this Article]

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