Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response.
Fluid shear stress caused by blood flow is a major determinant of vascular remodeling and arterial tone and can lead to development of atherosclerosis. The endothelial monolayer in vivo acts as a signal transduction interface for hemodynamic forces; these forces determine the shape, cytoskeletal organization, and function of endothelial cells, allowing the vessels to cope with physiological or pathological conditions. The Ras superfamily of GTPases have been revealed to be master regulators of many cellular activities. In particular, the GTPases RhoA, Rac1, and Cdc42 are known to regulate cell shape changes through effects on the cytoskeleton, but their ability to influence polarity, microtubule dynamics, and transcription factor activity is just as significant. Shear stress modulates the activity of small GTPases, which are critical for both cytoskeletal reorganization and changes in gene expression in response to shear stress. The goal of this article is to review what is known about Ras and more so about Rho GTPases in mechanotransduction and the responses of cells to fluid flow. Several distinct signaling pathways can be coordinately activated by flow, and small GTPases are strongly implicated in some of them; thus possible connections will be explored and a unifying hypothesis offered.
Tzima
Eleni
E
Department of Cell and Molecular Physiology, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA. etzima@med.unc.edu
D000818:Animals; D001775:Blood Circulation; D002199:Capillary Permeability; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007382:Intermediate Filaments / Q000502:physiology; D033081:Shear Strength; D015398:Signal Transduction; D013314:Stress, Mechanical; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins