Item Details

Abluminal Stimulation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes and Stabilizes Endothelial Sprout Formation

Lenz, Steven
Format
Thesis/Dissertation; Online
Author
Lenz, Steven
Advisor
Botchwey, Edward
Abstract
Local delivery of lipid mediators has become a promising new approach for therapeutic angiogenesis and regenerative medicine. In this study, we investigated how gradient stimulation (either abluminal/distal or luminal/proximal) of engineered microvessels with sphingosine 1-phosphate (S1P) receptor subtype-targeted molecules effects endothelial sprout growth using a microfluidic device. Our studies show distal stimulation of microvessels with FTY720, an S1P1/3 selective agonist, promotes both arterial and venular sprout growth, whereas proximal stimulation does not. Using pharmacological antagonists of S1P receptor subtypes, we further show that S1P3 functionality is necessary for VEGF-induced sprouting, and confirmed these findings ex vivo using a murine aortic ring assay in S1P3-/- deficient mice. S1P3 agonist stimulation enhanced vascular stability for both cell types via upregulation of the interendothelial junction protein VE-cadherin. Lastly, S1P3 activation under flow promoted arterial sprouting and branching while decreasing migratory cell fate in the microfluidic device. We used an in vivo murine dorsal skinfold window chamber model to confirm S1P3’s role in neovascular branching. Together, these data suggest that a distal transendothelial gradient of S1P1/3-targeted drugs is an effective technique for both enhancing and stabilizing capillary morphogenesis in angiogenic applications.
Date Received
20131214
Published
University of Virginia, Department of Biomedical Engineering, MS (Master of Science), 2013
Published Date
2013-12-12
Degree
MS (Master of Science)
Collection
Libra ETD Repository
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