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Regulation of Endothelial Cell Apoptosis by Vascular Endothelial Growth Inhibitor (VEGI) and Death Receptor 3 (DR3)

Grimaldo, Sammy (2008) Regulation of Endothelial Cell Apoptosis by Vascular Endothelial Growth Inhibitor (VEGI) and Death Receptor 3 (DR3). Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBlair, Harry Chcblair@imap.pitt.eduHCBLAIR
Committee MemberJohnson, Danjohnsond@pitt.eduJOHNSOND
Committee MemberLi,
Committee MemberVujanovic, Nikola
Committee MemberCheng,
Date: 27 August 2008
Date Type: Completion
Defense Date: 25 July 2008
Approval Date: 27 August 2008
Submission Date: 20 August 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Death Receptor; endothelial apoptosis; IKK; NF-kappaB; TNF superfamily; VEGI
Other ID:, etd-08202008-134518
Date Deposited: 10 Nov 2011 20:00
Last Modified: 15 Nov 2016 13:49


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