title: Mechanotransduction by endothelial cells is locally generated, direction-dependent, and ligand-specific.
abstract: Vascular endothelial cells display a wide panel of responses to changes in the shear stress that is exerted on them by blood flow. How sensory mechanisms convey information about flow conditions and how this information is integrated remains poorly understood. The issue is confounded by: (1) a large number of potential force sensors, (2) difficulties in differentiating these sensors from downstream sites of signal integration, and (3) the complexities inherent in understanding how forces are transmitted from the apical surface of the cell via the cytoskeleton to intracellular sites. As a consequence, neither the structures that sense force nor the nature of the forces that loads them have been clearly defined. In this study, we employed magnetic microspheres coated with ligands that bind integrin subsets (RGD peptides or type I collagen) or PECAM-1 to discriminate the downstream signaling effects of different sensor molecules and mechanisms for how they are loaded. We found that application of force to these transmembrane molecules elicited biologically important signaling (ERK1/2, AKT, and GSK-3beta phosphorylation), and downstream biological responses that depended on the following two factors: (1) the ligand that transmitted force and (2) the direction in which force was applied. These findings indicate that ligands locally generate different shear-induced responses in endothelium that depend on how force is delivered.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. marc.chretien@utoronto.ca
authors.forename: Marc L
authors.initials: ML
authors.lastname: Chrétien
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Moira R
authors.initials: MR
authors.lastname: Jackson
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.forename: B Lowell
authors.initials: BL
authors.lastname: Langille
mesh_terms: D000107:Acetylation; D000818:Animals; D001696:Biomechanical Phenomena; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D040542:Mechanotransduction, Cellular; D008863:Microspheres; D008870:Microtubules / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012995:Solubility; D013314:Stress, Mechanical; D034421:Sus scrofa
chemical_list: D016023:Integrins; D008024:Ligands; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3