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.
Highlights
The blood vessel system, consisting of arteries, veins and interconnecting capillaries, can deliver oxygen, nutrients, metabolites and carry circulating blood cells to support human life
After checking the expression level of vegfaa[29,30,31], we found these cds[2] mutants with severe vascular defects expressed a higher level of vegfaa, compared to those with a weaker phenotype (Fig. 1c), which is opposite to our expectation
Different from that in the control mice, FOXO1 protein predominantly located in endothelial nuclei in the front area of retinal vasculature in Cds2iΔEC mice (3.4 folds increase, compared to Control), which could be further enhanced by additional Vascular endothelial growth factor-a (VEGFA) stimulation (9.1 folds increase, compared to control with recombinant VEGFA stimulation) that resulted in dramatically increased nucleus FOXO1 in blunted angiogenic front with significantly reduced sprouts (Fig. 5a–c)
Summary
The blood vessel system, consisting of arteries, veins and interconnecting capillaries, can deliver oxygen, nutrients, metabolites and carry circulating blood cells to support human life. Vascular growth is mainly governed by angiogenesis, a wellstudied process of new blood vessel formation from the existing vessels, and vasculogenesis, the de novo formation of blood vessels using stem cells, involving extracellular matrix remodeling, tip or stalk cell fate determination, endothelial cell migration, proliferation and the subsequent stabilization by mural cells[7]. This process is managed by numerous angiogenic signaling factors such as VEGFs, FGF2, PDGFs, etc.[8,9]. Activation of VEGFA signaling leads to activation of downstream signal arms, including PLCγ and PI3K, both of which utilize membrane lipid-phosphatidylinositol-4,5-bisphosphate (PIP2) to mediate signal transduction and exert their angiogenic effects[10]
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