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Updated: Dec 27, 2025
In Vitro Model of Coronary Angiogenesis
Published on: March 10, 2020
Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
Amber N Stratman1,2, Olivia M Farrelly1, Constantinos M Mikelis3,4
1Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
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.
Insights
Targeting phosphoinositide recycling in endothelial cells (EC) offers a novel anti-angiogenic strategy. Inhibiting this process, crucial for responding to vascular endothelial growth factor (VEGF), effectively reduces tumor growth and angiogenesis.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Anti-angiogenic therapies aim to inhibit tumor growth by targeting blood vessel formation.
- Tumor-derived pro-angiogenic factors can overwhelm current anti-angiogenic treatments.
- Endothelial cells (EC) rely on phosphoinositide resynthesis for signaling pathways, including those stimulated by vascular endothelial growth factor (VEGF).
Purpose of the Study:
- To investigate targeting phosphoinositide resynthesis in ECs as a novel anti-angiogenic strategy.
- To determine if inhibiting phosphoinositide recycling can overcome resistance to anti-angiogenic therapies.
- To explore the role of CDP-diacylglycerol synthase 2 in EC response to VEGF.
Main Methods:
- Utilized zebrafish and human endothelial cells in vitro to study phosphoinositide metabolism.
- Assessed the impact of CDP-diacylglycerol synthase 2 deficiency on EC response to VEGF.
- Employed murine tumor allograft models to evaluate the efficacy of inhibiting phosphoinositide recycling in vivo.
Main Results:
- Endothelial cells deficient in CDP-diacylglycerol synthase 2 showed heightened sensitivity to VEGF stimulation due to impaired phosphoinositide resynthesis, including phosphatidylinositol-(4,5)-bisphosphate (PIP2).
- This impairment led to exacerbated defects in angiogenesis and angiogenic signaling.
- Systemic or EC-specific suppression of phosphoinositide recycling in tumor models significantly reduced tumor growth and angiogenesis.
Conclusions:
- Inhibition of phosphoinositide recycling represents a promising anti-angiogenic approach.
- This strategy leverages the tumor's own signaling environment to impair EC function.
- Targeting phosphoinositide metabolism offers a potential therapeutic avenue for cancer treatment.
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