Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition
| Autor: | Xuri Li, Hanru Ying, Yun-Chi Tang, Luyang Yu, Cong Fu, Weijun Pan, Li Dantong, Wencao Zhao, Wenjuan Zhang, Xiaoxi Lin, Mengye Cao, Dianqing Wu, Jun Qin, Le Cao, Lin Li, Haonan Qi, Xiaolong Zhu, Tao P. Zhong, Yimei Hao, Wenzhi Xue, Shuang Wu |
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| Rok vydání: | 2019 |
| Předmět: |
Vascular Endothelial Growth Factor A
endocrine system Endothelium Angiogenesis Melanoma Experimental Neovascularization Physiologic FOXO1 Vascular Regression Article Neovascularization Mice chemistry.chemical_compound Cell Line Tumor Neoplasms medicine Animals Humans Phosphatidylinositol Molecular Biology Zebrafish Mice Knockout Neovascularization Pathologic biology Growth factor signalling Endothelial Cells Cell Biology Zebrafish Proteins biology.organism_classification Nucleotidyltransferases Vascular endothelial growth factor A medicine.anatomical_structure chemistry Diacylglycerol Cholinephosphotransferase Cancer research medicine.symptom Tumour angiogenesis |
| Zdroj: | Cell Research |
| ISSN: | 1748-7838 1001-0602 |
| DOI: | 10.1038/s41422-019-0229-5 |
| Popis: | The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression. |
| Databáze: | OpenAIRE |
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