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.
内皮细胞的信令刺激的反应是血管的形态发生,内环境稳定和功能是至关重要的。血管内皮生长因子A(VEGFA)已被普遍公认的促血管生成因子在脊椎动物的发育,生理和病理条件几十年。此处我们报告一个新的发现,即CDP二酰基甘油合成酶-2(CDS2),代谢酶对照磷酸肌醇回收基因切除,开关VEGFA的从促进血管发生意外诱导血管退化信令的输出。实时成像分析发现的血管生成内皮的反向迁移在CDS2突变斑马鱼在VEGFA刺激的存在下,和内皮回归也发生在出生后视网膜和在小鼠中植入的肿瘤模型。在肿瘤模型中,CDS2缺乏增强的肿瘤分泌VEGFA,后者又捕获肿瘤成VEGFA诱导的血管退化状况的水平,导致肿瘤生长的抑制。在不存在CDS2控制磷酸肌醇代谢的机械地,VEGFA刺激减少磷脂酰肌醇(4,5)-bisphosphate(PIP2)的可用性,随后使磷脂酰肌醇(3,4,5) - 三磷酸(PIP3)缺乏和FOXO1激活触发回归的CDS2空内皮。因此,我们的数据表明,VEGFA对脉管系统的影响是依赖于上下文的,并且可以从血管生成被转化为血管退化。在不存在CDS2控制磷酸肌醇代谢的刺激VEGFA降低磷脂酰肌醇(4,5)-bisphosphate(PIP2)的可用性,随后使磷脂酰肌醇(3,4,5) - 三磷酸(PIP3)缺乏和FOXO1激活CDS2的触发回归-null内皮。因此,我们的数据表明,VEGFA对脉管系统的影响是依赖于上下文的,并且可以从血管生成被转化为血管退化。在不存在CDS2控制磷酸肌醇代谢的刺激VEGFA降低磷脂酰肌醇(4,5)-bisphosphate(PIP2)的可用性,随后使磷脂酰肌醇(3,4,5) - 三磷酸(PIP3)缺乏和FOXO1激活CDS2的触发回归-null内皮。因此,我们的数据表明,VEGFA对脉管系统的影响是依赖于上下文的,并且可以从血管生成被转化为血管退化。
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