Abstract
Shear stress is one of mechanical constraints which are exerted by blood flow on endothelial cells (ECs). To adapt to shear stress, ECs align in the direction of flow through adherens junction (AJ) remodeling. However, mechanisms regulating ECs alignment under shear stress are poorly understood. The scaffold protein IQ domain GTPase activating protein 1 (IQGAP1) is a scaffold protein which couples cell signaling to the actin and microtubule cytoskeletons and is involved in cell migration and adhesion. IQGAP1 also plays a role in AJ organization in epithelial cells. In this study, we investigated the potential IQGAP1 involvement in the endothelial cells alignment under shear stress. Progenitor-derived endothelial cells (PDECs), transfected (or not) with IQGAP1 small interfering RNA, were exposed to a laminar shear stress (1.2 N/m2) and AJ proteins (VE-cadherin and β-catenin) and IQGAP1 were labeled by immunofluorescence. We show that IQGAP1 is essential for ECs alignment under shear stress. We studied the role of IQGAP1 in AJs remodeling of PDECs exposed to shear stress by studying cell localization and IQGAP1 interactions with VE-cadherin and β-catenin by immunofluorescence and Proximity Ligation Assays. In static conditions, IQGAP1 interacts with VE-cadherin but not with β-catenin at the cell membrane. Under shear stress, IQGAP1 lost its interaction from VE-cadherin to β-catenin. This “switch” was concomitant with the loss of β-catenin/VE-cadherin interaction at the cell membrane. This work shows that IQGAP1 is essential to ECs alignment under shear stress and that AJ remodeling represents one of the mechanisms involved. These results provide a new approach to understand ECs alignment under to shear stress.
Highlights
Endothelial cells (ECs) are continuously exposed in vivo to mechanical stress
As far as shear stress partially disassembles adherens junction (AJ) in ECs [1], we investigated whether IQ domain GTPase activating protein 1 (IQGAP1) was involved in AJ under shear stress conditions in human progenitor derived endothelial cells (PDECs)
Progenitor-derived endothelial cells (PDECs) were subjected to a laminar shear stress of 1.2 N/m2 corresponding to an arterial blood flow
Summary
Endothelial cells (ECs) are continuously exposed in vivo to mechanical stress (tangential fluid shear stress, cyclic circumferential strain and blood pressure). When exposed to fluid shear stress, mature ECs and ECs derived from endothelial progenitor cells become elongated and aligned in the direction of flow, which involves AJ reshaping [1,2]. ECs alignment is associated to a translocation of the vascular endothelial cadherin (VE-cadherin) and b-catenin, inducing the disruption of the AJ [3]. The mechanosensory and mechanotransducer complex of shear stress at cell-cell junction consists of PECAM-1, vascular endothelial growth factor receptor-2 (VEGFR-2) and VEcadherin [5], which functions mainly as an adapter system. Shear stress stimulates the formation of the VEGFR-2/ VE-cadherin/b-catenin complex to activate MAP kinases pathway [7]. The same protein complex is formed after VEGF stimulation and implies IQGAP1 [8]
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