Abstract 20019: Tumor Necrosis Factor Alpha Inducible Protein Like 1 Promotes Angiogenesis by Inhibition of Endothelial Cell Apoptosis
During the initial phase of angiogenesis, proliferating endothelial cells (ECs) are highly susceptible to apoptosis and need rescuing by biological anti-apoptotic cues to ensure survival of the neovasculature. Although the molecular mechanisms that govern the formation of a vascular network have been studied intensively, specific angiogenic factors that regulate EC apoptosis still need to be further identified.
Using a transcriptomics approach to identify new regulators of angiogenesis, we identified tumor necrosis factor alpha inducible protein like 1 (TNFaip8L1), a gene of hitherto unknown function that was highly expressed in ECs. During mouse and zebrafish development, TNFaip8L1 expression was predominantly restricted to angioblasts and adult ECs. In vitro, overexpression of TNFaip8L1 using a lentivirus enhanced the endothelial capacity to form tubes (P<0.05, n=6) in HUVECs. In vivo in the murine retina, TNFaip8L1 overexpression resulted in enhanced formation of the vascular network (P<0.05, n=10). The observed effects of TNFaip8L1 were the result of specific inhibition of EC apoptosis in vitro (P<0.01, n=6) and in vivo (P<0.05, n=10). In contrast, knockdown of TNFaip8L1 expression using a shRNA lentivirus diminished endothelial network formation with increased EC apoptosis both in vitro (P<0.01, n=6) and in vivo (P<0.05, n=10). Further studies in vitro showed that TNFaip8L1 specifically inhibited TNFα-induced apoptosis in ECs (P<0.01, n=8), by inhibition of caspase 8 activity, leading up to quenching of the activation of caspase 3 (P<0.05, n=8) and enhanced EC survival.
Finally, vascular survival is crucial for safeguarding cardiac function after an ischemic insult. In line, the endothelial expression of TNFaip8L1 was strongly increased after a myocardial infarction (MI) (P<0.001, n=10), which suggests a role for TNFaip8L1 in the neovascularization response after MI.
These findings indicate for the first time that TNFaip8L1 functions as a new regulator of EC survival during vascular growth in development and ischemic heart disease, by specifically diminishing EC apoptosis.
Author Disclosures: D. Tempel: None. P. Burgisser: None. C. Cheng: None. G. Pasterkamp: None. H. Duckers: None.
- © 2014 by American Heart Association, Inc.