Advanced Search

Submit Manuscript

Volume 29, No 11, Nov 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 11, November 2019: 895-910   |  Open Access

ORIGINAL ARTICLES

Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition

Wencao Zhao1, Le Cao1, Hanru Ying 2, Wenjuan Zhang1, Dantong Li1, Xiaolong Zhu3, Wenzhi Xue1, Shuang Wu 1, Mengye Cao1,Cong Fu1, Haonan Qi1, Yimei Hao1, Yun-Chi Tang1, Jun Qin 1, Tao P. Zhong3, Xiaoxi Lin 2,4 , Luyang Yu5, Xuri Li6, Lin Li 7,Dianqing Wu8 and Weijun Pan 1,4

1Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China; 2Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China; 3Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, China; 4Innovative Research Team of High-level Local University in Shanghai, Shanghai, China; 5Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China; 6State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; 7State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, Shanghai, China and 8Department of Pharmacology, Vascular Biology and Therapeutic Program, School of Medicine, Yale University, New Haven, CT, USA
 Correspondence: Weijun Pan (weijunpan@sibs.ac.cn)These authors contributed equally: Wencao Zhao, Le Cao, Hanru Ying

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.


https://doi.org/10.1038/s41422-019-0229-5

FULL TEXT | PDF

Browse 813