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Mechanical Cyclic Strain Induces Ceramide Generation in Endothelial Cells

Hunter, Oriana C. (2009) Mechanical Cyclic Strain Induces Ceramide Generation in Endothelial Cells. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    The vascular endothelium is continuously subjected to a variety of mechanical and chemical stresses while it performs its duties in the maintenance of vascular permeability, tone, hemostasis, inflammation, and remodeling in health and disease. The mechanism by which endothelial cells respond to mechanical forces, or mechanotransduction, is not completely understood and is the subject of ongoing debate. Several theories involving proteins and reactive oxygen species have been proposed as components of the mechanotransduction process, however the role of the lipid microenvironment and lipid signaling remains largely unknown. We hypothesize that mechanical, uniaxial cyclic strain results in an increase in intracellular ceramide in vascular endothelial cells, which participates in signaling necessary to propagate mechanotransduction responses, potentially contributing to early events in the formation of atherosclerotic lesions. To evaluate this hypothesis, we used electrospray mass spectrometry to study the lipid microenvironment, particularly with regards to ceramide signaling, in endothelial cells in response to cyclic strain within and beyond the physiological range, so as to gain a better understanding of the events that may ultimately contribute to endothelial dysfunction. The findings of these studies have elucidated the time scale of the ceramide response and the ceramide biosynthetic and metabolic pathways that occur during the early response to cyclic strain. Ceramide signaling results from distinct signaling events associated with nSMase, aSMase, and de novo ceramide synthesis. The nSMase signaling event appears to be necessary for the later de novo event to occur. The endothelial response to cyclic strain is sensitive to strain magnitude, resulting in ceramide elevation at levels both above and below physiological strain magnitudes, suggestive of a wide variety of arterial pathological states. These findings help to elucidate the early events in the mechanotransduction response to cyclic strain and represent a step towards bridging our understanding of the relationship between mechanotransduction and inflammation as it relates to endothelial cell activation and dysfunction and vascular disease. Establishment of the involvement of the ceramide biosynthetic pathway in endothelial cells and the vascular environment provides us with new biomarkers and therapeutic targets to potentially protect against vascular activation, dysfunction, and atherogenesis.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairAmoscato, Andrew A
    Committee MemberVorp, David A
    Committee MemberRabinowich, Hannah
    Committee MemberLotze, Michael T
    Title: Mechanical Cyclic Strain Induces Ceramide Generation in Endothelial Cells
    Status: Unpublished
    Abstract: The vascular endothelium is continuously subjected to a variety of mechanical and chemical stresses while it performs its duties in the maintenance of vascular permeability, tone, hemostasis, inflammation, and remodeling in health and disease. The mechanism by which endothelial cells respond to mechanical forces, or mechanotransduction, is not completely understood and is the subject of ongoing debate. Several theories involving proteins and reactive oxygen species have been proposed as components of the mechanotransduction process, however the role of the lipid microenvironment and lipid signaling remains largely unknown. We hypothesize that mechanical, uniaxial cyclic strain results in an increase in intracellular ceramide in vascular endothelial cells, which participates in signaling necessary to propagate mechanotransduction responses, potentially contributing to early events in the formation of atherosclerotic lesions. To evaluate this hypothesis, we used electrospray mass spectrometry to study the lipid microenvironment, particularly with regards to ceramide signaling, in endothelial cells in response to cyclic strain within and beyond the physiological range, so as to gain a better understanding of the events that may ultimately contribute to endothelial dysfunction. The findings of these studies have elucidated the time scale of the ceramide response and the ceramide biosynthetic and metabolic pathways that occur during the early response to cyclic strain. Ceramide signaling results from distinct signaling events associated with nSMase, aSMase, and de novo ceramide synthesis. The nSMase signaling event appears to be necessary for the later de novo event to occur. The endothelial response to cyclic strain is sensitive to strain magnitude, resulting in ceramide elevation at levels both above and below physiological strain magnitudes, suggestive of a wide variety of arterial pathological states. These findings help to elucidate the early events in the mechanotransduction response to cyclic strain and represent a step towards bridging our understanding of the relationship between mechanotransduction and inflammation as it relates to endothelial cell activation and dysfunction and vascular disease. Establishment of the involvement of the ceramide biosynthetic pathway in endothelial cells and the vascular environment provides us with new biomarkers and therapeutic targets to potentially protect against vascular activation, dysfunction, and atherogenesis.
    Date: 25 September 2009
    Date Type: Completion
    Defense Date: 30 June 2009
    Approval Date: 25 September 2009
    Submission Date: 29 July 2009
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-07292009-120141
    Uncontrolled Keywords: ceramide; endothelial cells; mechanotransduction; strain
    Schools and Programs: Swanson School of Engineering > Bioengineering
    Date Deposited: 10 Nov 2011 14:54
    Last Modified: 06 Jun 2012 09:48
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-07292009-120141/, etd-07292009-120141

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