Hemodynamic Mechanisms Regulating Inflammatory Vascular Remodeling Public Deposited

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  • March 20, 2019
  • Givens, Chris
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Hemodynamic forces are critical regulators of vascular health and disease. Shear stress, the frictional force of blood flowing over the endothelium, is a major hemodynamic input into vascular function. For example, inflammatory blood flow patterns induce programs of intercellular signaling and gene expression that cause local vascular inflammation. Endothelial cells mediate the interactions between blood flow and blood vessels, and as such are exquisitely sensitive to forces. Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1), a well-known endothelial mechanosensor, is required for flow-induced endothelial inflammation, yet the signaling pathways connecting hemodynamics, PECAM-1, and vascular inflammation remain to be elucidated. This dissertation provides mechanistic insight into two PECAM-1 dependent inflammatory pathways: assembly of fibronectin (FN) into fibrils and the role of the adaptor protein Shc in inflammatory vascular remodeling. FN is an extracellular matrix protein that plays major roles in vascular development and disease. Required for embryonic development of the vascular plexus and heart, FN is also heavily deposited in atherosclerotic plaques and chronically inflamed vessels. As FN is known to sustain endothelial inflammation, knowledge of its assembly is critical to understanding vascular disease. In Chapter 2, I demonstrate that FN assembly is controlled by altered hemodynamics via PECAM-1. Additionally, I delineate a mechanism by which the small GTPase RhoA and β1 integrins regulate FN assembly in a PECAM-1 dependent manner. This is the first time that FN assembly has been mechanistically linked to hemodynamics, and suggests a route by which chronic inflammation may take hold in the endothelium. Vascular inflammation may result in remodeling of blood vessels, and depending on the physical cues at work, this remodeling may result in widening or narrowing of the blood vessels. The adaptor protein Shc is a known regulator of endothelial inflammation and outward vascular remodeling, and is phosphorylated upon the onset of shear. In Chapter 3, I demonstrate that Shc tyrosine phosphorylation is required for outward collateral remodeling in response to femoral artery ligation. I also demonstrate that Shc is required for atherogenesis, which is pathological inward remodeling of arteries in response to inflammatory flow. Critically, I show the involvement of Shc in atherogenesis to be responsive to changes in hemodynamics. These data suggest that Shc is a major regulator of vascular remodeling, as well as suggest potential targets for downstream vascular therapeutics.
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Rights statement
  • In Copyright
  • Bautch, Victoria
  • Tzima, Eleni
  • Cheney, Richard
  • Dudley, Andrew
  • Burridge, Keith
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017

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