Understanding PECAM-1-mediated mechanotransduction: from the protein to the vessel
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Collins, Caitlin. Understanding Pecam-1-mediated Mechanotransduction: From the Protein to the Vessel. University of North Carolina at Chapel Hill, 2013. https://doi.org/10.17615/ksqr-he98APA
Collins, C. (2013). Understanding PECAM-1-mediated mechanotransduction: from the protein to the vessel. University of North Carolina at Chapel Hill. https://doi.org/10.17615/ksqr-he98Chicago
Collins, Caitlin. 2013. Understanding Pecam-1-Mediated Mechanotransduction: From the Protein to the Vessel. University of North Carolina at Chapel Hill. https://doi.org/10.17615/ksqr-he98- Last Modified
- March 20, 2019
- Creator
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Collins, Caitlin
- Affiliation: School of Medicine, Department of Cell Biology and Physiology
- Abstract
- Hemodynamic forces are critical for endothelial cell (EC) function and vessel health. Platelet endothelial cell adhesion-1 (PECAM-1) has been identified as a critical endothelial mechanosensor that is required for transducing mechanical signals into intracellular signaling events; however, molecular mechanisms of PECAM-1-mediated mechanotransduction remain elusive. This dissertation investigates mechanosignaling and cellular responses directly linked to force transduction via PECAM-1. In recent years, there has been increasing interest to understand how cells respond to tension on mechanosensitive proteins. Numerous studies investigating force-bearing integrins and have revealed that the cell responds to exogenous force by increasing cell-generated force that is proportional to the applied force. This change in cellular force manifests as an adaptive cellular stiffening response that allows the cell to resist the strain of the applied force. While much work has focused on cellular responses linked to integrins, other mechanosensitive proteins are now being probed. In Chapter II, I demonstrate that tension on PECAM-1 also results in an adaptive stiffening response. Furthermore, I demonstrate that, surprisingly, the PECAM-1-mediated mechanoresponse is not locally restricted to regions proximal to the site of force application, but rather global in nature. These data suggest that, contrary to previous thoughts, a localized mechanical perturbation can globally affect signaling cascades and cellular phenotype. Mechanosensitive signaling within the endothelium is greatly influenced by the subendothelial matrix composition. In Chapter III, I investigate how the extracellular matrix (ECM) identity influences PECAM-1 mechanosignaling and cellular response to force. I demonstrate that, contrary to cells adherent on fibronectin, adhesion to collagen suppresses mechanical responsiveness to tension on PECAM-1, including adaptive stiffening and focal adhesion growth. I further identify PKA-mediated inactivation of RhoA as critical signaling axis that influences endothelial cell mechanics in response to tension on PECAM-1 and the physiological stimulus of fluid shear stress in vitro and in vivo. Taken together, the work presented in this dissertation advances our understanding of how endothelial cells integrate mechanical and extracellular matrix-specific cues and provides insight into how these factors may contribute to cellular phenotype in vivo.
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- 2013
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- In Copyright
- Advisor
- Tzima, Eleni
- Degree
- Doctor of Philosophy
- Graduation year
- 2013
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