Role of voltage-gated sodium channels in endothelial functions: Are they new vascular mechanosensors?

Introduction Voltage-gated sodium (NaV) channels are the hallmarks of excitable cells and involved in the cardiac excitation-contraction coupling. They are made of a pore-forming α subunit encoding by 9 genes (SCN1A–5A and 8A–11A) associated with β auxiliary subunits (SCN1B–4B genes). Interestingly, NaV channels are also expressed in non-excitable cells such as endothelial cells (EC) but their role is still not yet totally understood. Objective The aim of our study is to explore the role of NaV channels: – in proliferation and migration of EC, key process of vascular remodeling; – as new vascular mechanosensor since NaV channels have been shown to be sensitive to mechanical forces in cardiomyocytes and EC are constitutively exposed to physical forces created by blood flow, especially to shear stress. Methods Proliferation and migration of Human Umbilical Vein Endothelial Cells (HUVEC) were studied using the live-cell imaging system IncuCyte S3 and shear stress using the Ibidi pump system. Results Blocking NaV activity using the selective inhibitor tetrodotoxin inhibited significantly proliferation and migration of HUVEC. Exposition of HUVEC to a laminar shear stress (20 dynes/cm2) for 4 days induced a cell orientation in the flow direction and activated the atheroprotective signaling pathway (KLF2, eNOS, CYP1B1). Moreover, shear stress led to a profound transcriptional remodeling of different subunits of NaV channels on HUVEC with a down-regulation for the cardiac SCN5A by 5-fold and up-regulation for SCN8A, SCN9A, SCN1B and SCN3B. Since SCN3B is strongly upregulated by shear stress (9-fold), overexpression and silencing of this protein are currently under process in order to better understand the involvement of this transmembrane protein belong to Ig-CAM family in EC functions and its regulation. Conclusion Our data highlight the contribution of NaV channels in EC functions and suggest a new role of SCN3B as a potential vascular mechanotransductor.