Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Amber N. Stratman, Olivia M. Farrelly, Constantinos M. Mikelis, Mayumi F. Miller, Zhiyong Wang, Pham Van N., Andrew E. Davis, Margaret C. Burns, Sofia A. Pezoa, Daniel Castranova, Joseph J. Yano, Tina M. Kilts, George E. Davis, J. Silvio Gutkind and Brant M. Weinstein ()
Additional contact information
Amber N. Stratman: National Institute of Child Health and Human Development, National Institutes of Health
Olivia M. Farrelly: National Institute of Child Health and Human Development, National Institutes of Health
Constantinos M. Mikelis: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Mayumi F. Miller: National Institute of Child Health and Human Development, National Institutes of Health
Zhiyong Wang: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Pham Van N.: National Institute of Child Health and Human Development, National Institutes of Health
Andrew E. Davis: National Institute of Child Health and Human Development, National Institutes of Health
Margaret C. Burns: National Institute of Child Health and Human Development, National Institutes of Health
Sofia A. Pezoa: National Institute of Child Health and Human Development, National Institutes of Health
Daniel Castranova: National Institute of Child Health and Human Development, National Institutes of Health
Joseph J. Yano: National Institute of Child Health and Human Development, National Institutes of Health
Tina M. Kilts: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
George E. Davis: University of South Florida School of Medicine
J. Silvio Gutkind: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Brant M. Weinstein: National Institute of Child Health and Human Development, National Institutes of Health

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14956-z

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