title: CCM proteins control endothelial β1 integrin dependent response to shear stress.
abstract: Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that β1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress. Indeed, we show that overexpression of the CCM complex, an inhibitor of β1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to β1 integrin silencing. Conversely, depletion of CCM2 protein leads to an elongated "shear-stress-like" phenotype even in the absence of flow. Taken together, our findings reveal the existence of a balance between positive extracellular and negative intracellular signals, i.e. shear stress and CCM complex, for the control of β1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress.
authors.affiliation: INSERM, Institut Albert Bonniot, F-38000 Grenoble, France Université Grenoble Alpes, Institut Albert Bonniot, F-38000 Grenoble, France.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Macek Jilkova
authors.affiliation: INSERM, Institut Albert Bonniot, F-38000 Grenoble, France Université Grenoble Alpes, Institut Albert Bonniot, F-38000 Grenoble, France CNRS ERL 5284, F-38042 Grenoble, France.
authors.forename: Justyna
authors.initials: J
authors.lastname: Lisowska
authors.affiliation: INSERM, Institut Albert Bonniot, F-38000 Grenoble, France Université Grenoble Alpes, Institut Albert Bonniot, F-38000 Grenoble, France CNRS ERL 5284, F-38042 Grenoble, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Manet
authors.affiliation: CNRS/Université Grenoble 1, LIPhy, UMR 5588, F-38041 Grenoble, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Verdier
authors.affiliation: Aix-Marseille Université, CNRS, Centrale Marseille, IRPHE UMR 7342, F-13384, Marseille, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Deplano
authors.affiliation: CNRS UMR5521, 3SR, Université Joseph Fourier Grenoble-INP, Grenoble, F-38042, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Geindreau
authors.affiliation: INSERM, Institut Albert Bonniot, F-38000 Grenoble, France Université Grenoble Alpes, Institut Albert Bonniot, F-38000 Grenoble, France CNRS ERL 5284, F-38042 Grenoble, France eva.faurobert@ujf-grenoble.fr alain.duperray@ujf-grenoble.fr.
authors.forename: Eva
authors.initials: E
authors.lastname: Faurobert
authors.affiliation: INSERM, Institut Albert Bonniot, F-38000 Grenoble, France Université Grenoble Alpes, Institut Albert Bonniot, F-38000 Grenoble, France CNRS ERL 5284, F-38042 Grenoble, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Albigès-Rizo
authors.affiliation: INSERM, Institut Albert Bonniot, F-38000 Grenoble, France Université Grenoble Alpes, Institut Albert Bonniot, F-38000 Grenoble, France eva.faurobert@ujf-grenoble.fr alain.duperray@ujf-grenoble.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Duperray
keywords: CCM; Mechanotransduction; Shear stress; β1 integrin