Vegfa signaling regulates diverse artery/vein formation in vertebrate vasculatures

Jin, Da-Qing; Zhu, Diqi; Fang, Yanwen; Chen, Yiwei; Yu, Gaihong; Pan, Weijun; Liu, Dong; Li, Fen; Zhong, Tao

doi:10.1016/j.jgg.2017.07.005

Cited by 24 publications

(18 citation statements)

References 29 publications

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“…Zebrafish maintenance and breeding were performed by standard methods 85 . The transgenic line Tg(fli1a:eGFP), Tg(hsp: vegfaa), Tg(fli1a:gal4), Tg(tp1:dsGFP), Tg(HuC:gal4), Tg(fli1a:ngfp) and Tg(uas:GCaMP5) were described previously 14,32,[86][87][88] . Most experiments in this study were carried out in the embryos generated by outcross of Tg(hsp:vegfaa) with other lines if possible.…”

Section: Methodsmentioning

confidence: 99%

“…1d). To further confirm this phenomenon with statistical analysis, cds2 mutants were crossed into Tg(hsp:vegfaa) transgenic background 32 . After heat shock induction, vegfaa expression reached a peak level in 4 h and then remained at least 5 folds higher compared to that in siblings without VEGFA induction (Supplementary information, Fig.…”

Section: Vegfa Triggers Vessel Regression In Cds2-deficient Zebrafishmentioning

confidence: 99%

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

et al. 2019

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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 tumorsecreted 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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Section: Methodsmentioning

confidence: 99%

Section: Vegfa Triggers Vessel Regression In Cds2-deficient Zebrafishmentioning

confidence: 99%

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

et al. 2019

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“…For instance, zebrafish mutants in kdrl, plcg or treated with the Vegf pathway inhibitor SU5416 display an absence of ERK phosphorylation (Fish et al, 2017; Shin et al, 2016), together with a reduction in ISV outgrowth and cell numbers. Similarly, mutants in vegfaa show a severe reduction in EC numbers and migration during ISV formation (Jin et al, 2017), phenotypes also seen in VEGFA mutant mice (Carmeliet et al, 1996; Ferrara et al, 1996). Therefore, it has been difficult in animal models to dissect out the individual contribution of a given gene or its downstream pathway components to either process.…”

Section: Discussionmentioning

confidence: 85%

Distinct Vegfa isoforms control endothelial cell proliferation through PI3 kinase signalling mediated regulation of cdkn1a/p21

Lange

Leonard

Ohnesorge

et al. 2020

Preprint

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SUMMARYThe formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa affected endothelial cell migration and proliferation. Surprisingly, mutations in vegfab specifically reduced endothelial cell proliferation. Analysis of downstream signaling revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutants. The cell cycle inhibitor cdkn1a/p21 was upregulated in vegfab deficient embryos. Accordingly, reducing cdkn1a/p21 restored endothelial cell proliferation. Together, these results suggest that extracellular matrix bound Vegfa acts through PI3K signaling to specifically control endothelial cell proliferation during angiogenesis independently of MAPK (ERK) regulation.

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“…VEGFA regulates vascular development during embryogenesis and organ formation under physiological condition [28]. Disruption of this gene in mice resulted in abnormal embryonic blood vessel formation.…”

Section: Discussionmentioning

confidence: 99%

Association between Single Nucleotide Polymorphisms in Cardiovascular Developmental Critical Genes and Hypertension: A Propensity Score Matching Analysis

Zhao

Gong

Gao

et al. 2020

International Journal of Hypertension

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Cardiovascular development critical genes are key determinants in cardiovascular diseases. We hypothesize that SNPs in these genes may play critical roles in the development of hypertension. erefore, we enrolled 516 paired hypertension patients and controls in a total of 2,742 subjects in a cross-sectional population study by the propensity score matching (PSM) method. Twentyone SNPs from 5 cardiovascular developmental related genes were detected by the improved multiplex ligase detection reaction (iMLDR) method. Conditioned logistic regression under three different genetic models, namely, additive model, dominant model, and recessive model, was performed. e odds ratio (ORs) and 95% confidence intervals (95% CIs) were used to estimate the associations of SNPs with hypertension. We found that the distribution of genotypes at rs833061, rs3025010, and rs699947 within the VEGFA gene and the distribution of alleles at rs3025010 in hypertension subjects were different from those in controls. Both rs833061 and rs3025010 were associated with hypertension in crude models, but only rs3025010 remains associated with hypertension after adjusting with confounding factors in the additive model and the dominant model. We also found that hypertension subjects with C/T and C/C genotypes at rs3025010 had lower SBP and DBP levels. In addition, rs3025010 could interact with rs6784267 within the CCM3 gene in the association. In conclusion, our findings suggest that rs3025010 may play a role in the pathogenesis of hypertension, which may be a potential target for individualized prevention and treatment of hypertension.

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Vegfa signaling regulates diverse artery/vein formation in vertebrate vasculatures

Cited by 24 publications

References 29 publications

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

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

Distinct Vegfa isoforms control endothelial cell proliferation through PI3 kinase signalling mediated regulation of cdkn1a/p21

Association between Single Nucleotide Polymorphisms in Cardiovascular Developmental Critical Genes and Hypertension: A Propensity Score Matching Analysis

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