Soutenance de thèse Surya Batta

Hemodynamic forces play an important role in the vascular network development and homeostasis. Altered hemodynamic forces have been shown to associate with vascular disorders such as atherosclerosis and aneurysms. Cytoskeletal rearrangement is the primary response of vascular cells such as endothelial cells (ECs) and smooth muscle cells (VSMCs) to  hemodynamic forces and irregular cytoskeletal arrangements has been observed in areas prone to vascular disorders in vivo. Guanine nucleotide exchange factors (GEFs) mediate spatio-temporal activation of small-GTPases (RhoA, Rac1, Cdc42), which are key players of cytoskeletal dynamics. Identifying mechanosensitive GEFs may provide new potential therapeutic targets to treat vascular disorders. RNA sequencing performed on ECs and VSMCs subjected to various shear stress and cyclic stretch levels respectively, identified ARHGEF18, ARHGEF40 in ECs and NET1 in VSMCs as potential mechanosensitive GEFs. In ECs, pathological (3.6 & 36 dynes/cm2) shear stress reduced Arhgef18 activity compared to physiological (16 dynes/cm2) shear stress. In our hands, Arhgef18 interact with RhoA only but knocking down of Arhgef18 reduces both RhoA and Rac1 activity. Moreover, ECs silenced for Arhgef18 showed reduced adhesion and migration under static conditions. Under physiological shear stress conditions, loss of   Arhgef18 altered cell alignment and junctional protein localization. Furthermore, knockdown of Arhgef18 significantly reduced TNFα mediated COX2 expression. These findings Identified Arhgef18 as a potential mechanosensitive GEF that plays important role in ECs physiology and inflammation thereby vascular diseases.