Vascular Endothelial Growth Inhibitor (VEGI) is an endothelial cell autocrine factor and a member of the tumor necrosis family of ligands. VEGI is able to specifically inhibit endothelial cell growth and is an efficient inhibitor of angiogenesis. The molecular mechanisms of VEGI activity on endothelial cells remain undefined. Here we focused on two important steps in the signal transduction of VEGI. We first determined a role of NF-κB in VEGI-induced apoptosis. We found that inhibition of the NF-κB pathway resulted in an increased apoptotic potential of VEGI. We conclude that the NF-κB pathway plays a role in suppressing the apoptotic potential of VEGI. We next investigated the receptor responsible for VEGI-induced endothelial cell apoptosis. DR3 is a receptor for VEGI and thus we first focused on confirming if DR3 is the receptor responsible for VEGI-mediated endothelial cell death. We determined VEGI had diminished apoptotic activity in endothelial cells that are depleted of DR3 by siRNA. However, it was determined that the apoptotic stimuli, LPS and TNFα, were also unable to mediate cell death in DR3-depleted endothelial cells. We conclude that DR3 is mediating an intracellular event that is involved in controlling the apoptotic pathway. This is a novel role of DR3 that is yet to be described. However, this role of DR3 interferes with our analysis of the ligand/receptor relationship and therefore we were unable to confirm that DR3 is the receptor responsible for VEGI-induced apoptosis. We also provide preliminary evidence that VEGI is utilizing an unknown receptor to mediate NF-κB activation. We therefore provide several mechanisms to control VEGI-mediated endothelial cell death, one being the activation of NF-κB to suppress the apoptotic potential of VEGI and the needed presence of DR3 for VEGI to initiate apoptosis, a role that is possibly independent of ligand binding.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08202008-134518 |
| Date | 27 August 2008 |
| Creators | Grimaldo, Sammy |
| Contributors | Harry C. Blair, Luyuan Li, Nikola L. Vujanovic, Shiyuan Cheng, Dan Johnson |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08202008-134518/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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