Syndecan-1 in vascular mechanosensing

The cells of vascular tissues are subject to biophysical and biochemical cues from their microenvironment. These cues are relayed to cells via adhesion receptors on the cell surface to components of the extracellular matrix, cytoskeleton-linked proteins and stretch-sensitive ion channels. These cues can influence cell alignment, morphology, proliferation and differentiation. A major challenge in engineering materials for vascular grafts is to understand and harness the mechanosensory mechanisms of cells to develop more effective therapies. Syndecan-1 is a transmembrane cell surface proteoglycan that has been shown to play a role in flow sensation in the glycocalyx of arteries, affecting endothelial cell proliferation and phenotype. Because of its interactions with cytoskeletal and focal adhesion associated proteins, it may serve as a mechanosensor for substrate-mediated cues. To date, the mechanisms of mechanical environment sensation through syndecan-1 are not well understood. This work tests the hypothesis that syndecan-1 is a key molecule in vascular cell mechanosensing and phenotype switching. We examine how cellular mechanosensing and adaptation to surfaces of various stiffness and nanotopography are affected by syndecan-1. We determine what players of cytoskeletal rearrangement and nanotopography sensation are affected by syndecan-1 in this context. We also developed FRET-based syndecan-1 tension sensors to visualize syndecan-1 activation during mechanosensation and determine what domains of syndecan-1 are important to its mechanosensory function in vitro. Our findings demonstrate that syndecan-1 tension is modulated by substrate- and shear-stress-mediated cues