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Dissertation
Endothelial cell mechanotransduction in diabetes: effect of glycated collagen, hyperglycemia, and hypoglycemia on shear stress response and adhesion strength
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2012
DOI:
https://doi.org/10.17918/etd-3844
Abstract
Diabetes is a worldwide epidemic, and people with diabetes suffer from morbidity and mortality related to cardiovascular disease. Vascular endothelial cells are mechanosensitive to fluid shear stress, and hyperglycemia, a hallmark of diabetes, affects endothelial cell function. Clinical evidence suggests interaction between mechanics and high glucose, since diabetic patients have accelerated atherosclerosis. The central objective of this thesis is to examine how native and glycated collagen substrates and hyper- and hypoglycemic conditions alter endothelial cell fluid shear stress response and adhesion strength. Endothelial cells were cultured on either native or glycated collagen coated substrates, and in three glucose conditions: low (1 mM), normal (5.5 mM) and high glucose (33 mM). Endothelial shear stress response was studied using a parallel plate flow system, and a spinning disc apparatus was used to quantify endothelial cell adhesion strength. Glycated collagen substrates, low glucose medium, and high glucose medium prevented endothelial cell alignment and reduced nitric oxide production with shear stress exposure and also increased endothelial cell adhesion strength. While these three diabetic conditions shared impaired signaling pathways, including decreased focal adhesion kinase and endothelial nitric oxide synthase phosphorylation, the underlying mechanisms for altered cell response were different. Endothelial cells used V 3 integrins to attach to glycated collagen instead of 2 1 integrins to attach to native collagen, which affected mechanotransduction pathways and adhesion strength. In high glucose, endothelial cells produced increased reactive oxygen species and protein kinase C, which inhibited focal adhesion kinase phosphorylation. Endothelial cells in low glucose released vascular endothelial growth factor, which disrupted the mechanosensory complex and activated integrins. These results show that endothelial cell response to a physiologically relevant mechanical environment is dysfunctional under hyperglycemia conditions. Clinically, endothelial cell phenotypic changes in altered glucose play a critical role in the early, accelerated atherosclerosis seen in diabetic patients. This research confirms the importance of strict glucose control to reduce diabetic vascular complications.
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Details
- Title
- Endothelial cell mechanotransduction in diabetes
- Creators
- Steven Frank Kemeny - DU
- Contributors
- Alisa Morss Clyne (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Engineering (1970-2026); Mechanical Engineering (and Mechanics) [Historical]; Drexel University
- Other Identifier
- 3844; 991014632571504721