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.
|Advisor:||Amoscato, Andrew A.|
|School:||University of Pittsburgh|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 70/12, Dissertation Abstracts International|
|Subjects:||Molecular biology, Biomedical engineering|
|Keywords:||Ceramide generation, Cyclic strain, Endothelial cells, Mechanotransduction|
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