2. Academic Validation
  3. Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition

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

  • Cell Res. 2019 Nov;29(11):895-910. doi: 10.1038/s41422-019-0229-5.
Wencao Zhao  # 1,  Le Cao  # 1,  Hanru Ying  # 2,  Wenjuan Zhang 1,  Dantong Li 1,  Xiaolong Zhu 3,  Wenzhi Xue 1,  Shuang Wu 1,  Mengye Cao 1,  Cong Fu 1,  Haonan Qi 1,  Yimei Hao 1,  Yun-Chi Tang 1,  Jun Qin 1,  Tao P Zhong 3,  Xiaoxi Lin 2 4,  Luyang Yu 5,  Xuri Li 6,  Lin Li 7,  Dianqing Wu 8,  Weijun Pan 9 10
Affiliations

Affiliations

  • 1 Key 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.
  • 2 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai, China.
  • 4 Innovative Research Team of High-level Local University in Shanghai, Shanghai, China.
  • 5 Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 6 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
  • 7 State 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.
  • 8 Department of Pharmacology, Vascular Biology and Therapeutic Program, School of Medicine, Yale University, New Haven, CT, USA.
  • 9 Key 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. [email protected].
  • 10 Innovative Research Team of High-level Local University in Shanghai, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 31501519 DOI: 10.1038/s41422-019-0229-5
Abstract

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.

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