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NDRG1 activates VEGF-A-induced angiogenesis through PLCγ1/ERK signaling in mouse vascular endothelial cells
Kosuke Watari1, Tomohiro Shibata1, Hideaki Fujita2
1Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Abstract:
Many diseases, including cancer, have been associated with impaired regulation of angiogenesis, of which vascular endothelial growth factor (VEGF)-A is a key regulator. Here, we test the contribution of N-myc downstream regulated gene 1 (NDRG1) to VEGF-A-induced angiogenesis in vascular endothelial cells (ECs). Ndrg1-/- mice exhibit impaired VEGF-A-induced angiogenesis in corneas. Tumor angiogenesis induced by cancer cells that express high levels of VEGF-A was also reduced in a mouse dorsal air sac assay. Furthermore, NDRG1 deficiency in ECs prevented angiogenic sprouting from the aorta and the activation of phospholipase Cγ1 (PLCγ1) and ERK1/2 by VEGF-A without affecting the expression and function of VEGFR2. Finally, we show that NDRG1 formed a complex with PLCγ1 through its phosphorylation sites, and the inhibition of PLCγ1 dramatically suppressed VEGF-A-induced angiogenesis in the mouse cornea, suggesting an essential role of NDRG1 in VEGF-A-induced angiogenesis through PLCγ1 signaling.
Insights
N-myc downstream regulated gene 1 (NDRG1) is crucial for vascular endothelial growth factor (VEGF)-A-induced angiogenesis. NDRG1 deficiency impairs blood vessel formation in mice, highlighting its role in this vital process.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Angiogenesis, the formation of new blood vessels, is critical for development and disease, including cancer.
- Vascular endothelial growth factor (VEGF)-A is a primary regulator of angiogenesis.
- Impaired angiogenesis regulation is linked to various diseases, notably cancer.
Purpose of the Study:
- To investigate the role of N-myc downstream regulated gene 1 (NDRG1) in VEGF-A-induced angiogenesis.
- To determine NDRG1's contribution to vascular endothelial cell (EC) function in response to VEGF-A.
Main Methods:
- Utilized Ndrg1 knockout (Ndrg1-/-) mice to assess angiogenesis in corneal and dorsal air sac assays.
- Examined angiogenic sprouting from aorta explants in NDRG1-deficient ECs.
- Investigated the signaling pathways downstream of VEGF receptor 2 (VEGFR2), including phospholipase Cγ1 (PLCγ1) and ERK1/2 activation.
- Analyzed NDRG1-PLCγ1 complex formation via immunoprecipitation and phosphorylation site mapping.
Main Results:
- Ndrg1-/- mice displayed significantly reduced VEGF-A-induced angiogenesis in corneal assays.
- Tumor angiogenesis was diminished in a mouse dorsal air sac model when NDRG1 was deficient.
- NDRG1 deficiency in ECs inhibited angiogenic sprouting and blocked VEGF-A-mediated activation of PLCγ1 and ERK1/2, without altering VEGFR2 expression or function.
- NDRG1 was found to complex with PLCγ1 at its phosphorylation sites.
Conclusions:
- NDRG1 plays an essential role in VEGF-A-induced angiogenesis.
- NDRG1 mediates VEGF-A signaling through the PLCγ1 pathway.
- Targeting the NDRG1-PLCγ1 interaction may offer therapeutic strategies for diseases involving aberrant angiogenesis.
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