CCM proteins control endothelial β1 integrin dependent response to shear stress

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 beta 1 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 beta 1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to beta 1 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 beta 1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress.