BME PhD Proposal Seminar: William Okech
The Role of Subendothelial ECM Fibronectin Mechanosignaling in Endothelial Cell Responses to Flow
Professor Ingrid Sarelius, Ph.D.
Atherosclerosis is a chronic inflammatory disease of the arterial wall and it is the leading cause of death in the developed world. Although multiple risk factors are associated with the progression of the disease, blood flow-induced shear stress has been shown to play an essential role in its initiation. Atherosclerotic lesions tend to preferentially develop in vascular regions (arterial curvatures and bifurcations) exposed to disturbed blood flow and these regions also exhibit an increase in both endothelial cell inflammatory signaling and extracellular matrix (ECM) fibronectin deposition in the basement membrane. Although previous studies have demonstrated a role for ECM fibronectin in endothelial cell responses to flow, the effect of module-specific signaling from ECM fibronectin has not been investigated. My preliminary data have established that a conformation-dependent, matricryptic, heparin-binding site within the first type III repeat of ECM fibronectin (FN III1H) is a critical component in endothelial cell shear stress mechanotransduction. Therefore, the goal of this proposal is to establish the role of ECM fibronectin and its matricryptic site (FNIII1H) in the process of calcium-dependent cytoskeletal reorganization (Specific Aim 1 & 2) and endothelial cell inflammatory signaling (Specific Aim 3) in response to flow. Utilizing engineered fibronectin matrix mimetics that allow for module-specific signaling from fibronectin and inhibitors of fibronectin matrix assembly, the relevant ECM fibronectin modules involved in these responses will be determined. Overall, we expect to demonstrate that ECM fibronectin is a mechanosensor that can convert mechanical stimuli into a biological signal via the conformation-dependent, matricryptic, heparin-binding site (FN III1H).