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    The Role of Caveolae in PECAM-1 Mechanotransduction

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    TETDEDXHeayn-temple-0225E-11814.pdf
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    Genre
    Thesis/Dissertation
    Date
    2014
    Author
    Heayn, Michelle Diane
    Advisor
    Rizzo, Victor
    Committee member
    Scalia, Rosario
    Eguchi, Satoru
    Kilpatrick, Laurie
    Park, Joon Young
    Department
    Physiology
    Subject
    Cellular Biology
    Biology, Molecular
    Biomechanics
    Atherosclerosis
    Caveolae
    Endothelial
    Pecam-1
    Shear Stress
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2991
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2973
    Abstract
    Altered fluid flow, which is found in branches and curvatures of arteries, results in abnormal forces on the endothelial cells (EC). These forces have been shown to alter EC gene expression and phenotype and to activate several cellular structures including G-proteins, ion channels, adhesion molecules, and caveolae. Recently, PECAM-1 has been implicated as the primary sensor of hemodynamic forces in EC. Shear stress rapidly induces tyrosine phosphorylation of PECAM-1 and the recruitment of SHP-2. These events appear to contribute to shear-activation of ERK1/2. Additionally, PECAM-1 has been shown to form a mechanosensory signaling complex with VE-cadherin, VEGFR2, and βcatenin which plays a role in adhesion molecule expression and regulation of NF-κB. Past work has shown that caveolae membrane domains also serve as mechanotransduction sites that regulate many of these same second messengers. Based on these novel observations, we hypothesize that the PECAM-1 mediated mechanotransduction requires caveolar membrane domains to effectively propagate mechano-signals. In this study, we intended to specifically test this hypothesis by 1) evaluating the role of caveolae in shear stress-induced PECAM-1 tyrosine phosphorylation, recruitment of SHP-2, and formation of a signaling complex with VE-cadherin, VEGFR2, and βcatenin and 2) determining the functional significance of PECAM-1 compartmentalization within caveolae with regard to changes in endothelial cell phenotype induced by atherogenic patterns of flow. Here, we have identified a pool of PECAM-1 which localizes within lipid rafts and caveolar membranes. This pool of PECAM-1 was shown to be activated by tyrosine phosphorylation and recruitment of mechanosignaling complex members in response to shear stress. We were also able to demonstrate complex formation in an in vivo model of disturbed blood flow. The significance of PECAM-1 compartmentalization to these membrane microdomains was demonstrated in endothelial cells treated with raft/caveolae disrupting compounds where shear stress-induced PECAM-1 tyrosine phosphorylation was markedly attenuated. Finally, we attempted to generate an adenovirus expressing a mutant form of PECAM-1 which was unable to target to lipid rafts in order to determine the importance of PECAM-1 localization in lipid rafts and caveolae on its downstream signaling in response to shear stress. Results from these studies provide new knowledge as to how endothelial cells respond to changing hemodynamic parameters, which could provide greater insight into how flow influences vascular homeostasis.
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