Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
- Stratman, A.N., Farrelly, O.M., Mikelis, C.M., Miller, M.F., Wang, Z., Pham, V.N., Davis, A.E., Burns, M.C., Pezoa, S.A., Castranova, D., Yano, J.J., Kilts, T.M., Davis, G.E., Gutkind, J.S., Weinstein, B.M.
- Nature communications 11: 1204 (Journal)
- Registered Authors
- Castranova, Dan, Davis, Andrew, Miller, Mayumi, Pham, Van, Stratman, Amber, Weinstein, Brant M.
- MeSH Terms
- Allografts/drug effects
- Angiogenesis Inhibitors/pharmacology*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Diacylglycerol Cholinephosphotransferase/deficiency
- Diacylglycerol Cholinephosphotransferase/metabolism
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism*
- Gene Deletion
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Mice, Knockout
- Models, Biological
- Neovascularization, Physiologic/drug effects
- Organ Specificity
- Signal Transduction
- Vascular Endothelial Growth Factors/metabolism*
- 32139674 Full text @ Nat. Commun.
Stratman, A.N., Farrelly, O.M., Mikelis, C.M., Miller, M.F., Wang, Z., Pham, V.N., Davis, A.E., Burns, M.C., Pezoa, S.A., Castranova, D., Yano, J.J., Kilts, T.M., Davis, G.E., Gutkind, J.S., Weinstein, B.M. (2020) Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling. Nature communications. 11:1204.
Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of pro-angiogenic signals in endothelial cells (EC), thus harnessing the tumor's own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes