Fig. 2.

Flow-responsive mechanosensory pathways. Changes in flow are detected within the endothelial cell through several mechanosensory pathways. There are broadly four key signalling cascades regulating gene expression. Membrane bound mechanosensory receptors, including G-protein coupled receptors (GPCR), Piezo1 and transient receptor potential vanilloid-type 4 (TRPV4) ion channels and glycocalyx members (including syndecan and glypican), induce changes in gene expression via the mitogen-activated protein kinase pathway (MEK5/ERK5). In addition, the VE-cadherin–PECAM-1–VEGFR2/3 mechanosensory complex [comprising of VE-cadherin, platelet endothelial cell adhesion molecule 1 (PECAM-1), and vascular endothelial growth factor receptor 2 and 3 (VEGFR2/3)] can induce a cascade of responses, through the activation of Src-dependent phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and subsequent activation of the protein kinase Akt. Integrin-associated pathways can also induce signalling cascade responses via the p130Cas Scaffold and ERK5, either in response to activation via Akt signalling or through detection in changes in extracellular matrix structures in response to flow. Finally, activation of calveolins within membrane calveolae is also capable of inducing vasodilatory responses, via the activation of membrane-bound calcium (Ca²⁺) channels. Cumulatively, these signalling cascades induce changes in gene expression and acute vasodilatory responses via elevation in nitric oxide (NO) and prostacyclin (PGI₂) production. Created with BioRender.com