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Thesis
Fibroblast growth factor-2 interaction with vascular cells and basement membrane under physiological fluid flow and diabetic hyperglycemia
Master of Science (M.S.), Drexel University
Apr 2010
DOI:
https://doi.org/10.17918/etd-3227
Abstract
Diabetes is a debilitating disease with a significant impact on global health. People with diabetes experience early and accelerated atherosclerosis and are at increased risk of restenosis. Though the pathogenesis of atherosclerosis and restenosis are complex, endothelial cells (EC), smooth muscle cells (SMC), and basement membrane (BM) play important roles in lesion development. Healthy EC regulate SMC function, but EC become dysfunctional in hyperglycemia or on glycated collagen, which may alter SMC regulation. Fibroblast growth factor-2 (FGF2), which is produced and released by EC and binds to heparan sulfate proteoglycans in the endothelial BM, may be critical to loss of vascular homeostasis. Experimental and computational models of BM-FGF2 binding kinetics under static conditions are well established in the literature but remain largely unexplored under flow. To investigate BM-FGF2 binding kinetics under fluid flow, BM-FGF2 equilibrium and associative binding were measured at various shear stresses. Surprisingly, BM-bound FGF2 increased up to a physiological arterial shear stress of 25 dynes/cm2, after which it decreased. These data suggest that FGF2 binding varies with shear stress possibly by a catch-slip mechanism, where applied force changes the dissociation constant to either promote ("catch") or reduce ("slip") binding. A computational model of BM-FGF2 interaction incorporating convective-diffusive transport and a surface binding reaction was also created. BM-bound FGF2 is released over time, after which FGF2 affects both EC and SMC. EC and SMC proliferation and intracellular signaling in response to FGF2 were investigated under hyperglycemic conditions, including for cells grown on glycated collagen or in high glucose media. Glycated collagen did not change EC proliferation or pERK signaling, however pAkt signaling decreased on glycated collagen. This suggests that glycated collagen may decrease FGF2 promotion of EC survival. SMC proliferation decreased on glycated collagen, while SMC cultured with FGF2 showed no difference in growth. Improved understanding of BM-FGF2 binding with flow serves as an initial step in a comprehensive model of FGF2 binding to BM and cells under fluid flow. Together with the observed altered FGF2 effects on vascular cells, these data motivate the development of improved growth factor treatments under physiological and disease conditions.
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Details
- Title
- Fibroblast growth factor-2 interaction with vascular cells and basement membrane under physiological fluid flow and diabetic hyperglycemia
- Creators
- Karl Vernon Reisig - DU
- Contributors
- Alisa Morss Clyne (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 3227; 991014632393104721