Mechanotransduction in the Endothelium: Role of Membrane Proteins and Reactive Oxygen Species in Sensing, Transduction, and Transmission of the Signal with Altered Blood Flow

SIGNIFICANCE: Changes in shear stress associated with alterations in blood flow initiate a signaling cascade that modulates the vascular phenotype. Shear stress is "sensed" by the endothelium via a mechanosensitive complex on the endothelial cell (EC) membrane that has been characterized as a "mechanosome" consisting of caveolae, platelet endothelial cell adhesion molecule (PECAM), vascular endothelial growth factor receptor 2 (VEGFR2), vascular endothelial (VE)-cadherin, and possibly other elements. This shear signal is transduced by cell membrane ion channels and various kinases and results in the activation of NADPH oxidase (type 2) with the production of reactive oxygen species (ROS). RECENT ADVANCES: The signaling cascade associated with stop of shear, as would occur in vivo with various obstructive pathologies, leads to cell proliferation and eventual revascularization. CRITICAL ISSUES AND FUTURE DIRECTIONS: Although several elements of mechanosensing such as the sensing event, the transduction, transmission, and reception of the mechanosignal are now reasonably well understood, the links among these discrete steps in the pathway are not clear. Thus, identifying the mechanisms for the interaction of the K(ATP) channel, the kinases, and ROS to drive long-term adaptive responses in ECs is necessary. A critical re-examination of the signaling events associated with complex flow patterns (turbulent, oscillatory) under physiological conditions is also essential for the progress in the field. Since these complex shear patterns may be associated with an atherosclerosis susceptible phenotype, a specific challenge will be the pharmacological modulation of the responses to altered signaling events that occur at specific sites of disturbed or obstructed flow.