Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

Huang, Chao‐Cheng; Kuo, Hsi-Kung; Wu, Pei-Chang; Cheng, Shih-Hsuan; Chang, Tzu‐Ting; Chang, Yu‐Chan; Kung, Mei-Lang; Wu, Deng‐Chyang; Chuang, Jiin‐Haur; Tai, Ming‐Hong

doi:10.1007/s10456-018-9596-7

Cited by 47 publications

(36 citation statements)

References 43 publications

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“…Whether the VEGFR2 signal is activated, we detected the phosphorylation level of VEGFR2 after activating CD137 signaling for a time point, 0, 2, 5, 10, 15, and 30 minutes and found that phosphorylated VEGFR2 (Tyr1173) was increased, achieving the maximum level at 10 minutes, which indicated that CD137 rapidly promoted VEGFR2 phosphorylation at Tyr1173 (Figures 2(d) and 2(e) ). Besides, activating the CD137 signal for 10 minutes promoted Akt and eNOS phosphorylation (Figures 2(f) and 2(g) ) both the downstream molecules of phosphorylated VEGFR2 [ 39 ]. And blocking CD137 signaling with inhibitory anti-CD137 antibody weakened the effects of CD137 signaling on VEGFR2 and Phospho-Akt (p-Akt, Ser473) and phospho-eNOS (p-eNOS, Ser1177) (Figures 2(f) and 2(g) ).…”

Section: Resultsmentioning

confidence: 99%

“…The deficiency in eNOS markedly decreased retinal neovascularization in a mouse model [ 55 ]. Additionally, Huang et al reported that soluble delta-like 1 homolog (DLK1) stimulated angiogenesis through Notch1/Akt/eNOS signaling in ECs [ 39 ]. CD137 signaling activating eNOS conforms to the studies on CD137 proangiogenesis effects [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

Zhang

Yin

et al. 2020

Mediators of Inflammation

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Combination of antiangiogenesis and immunotherapy may be an effective strategy for treatment of solid tumors. Our previous work reported that activation of CD137 signaling promotes intraplaque angiogenesis. A number of studies have demonstrated that vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for angiogenesis. However, it is unknown whether CD137-mediated angiogenesis is related to VEGFR2. In this study, we investigated the effect of CD137 on the VEGFR2 expression and explored the underlying mechanisms of CD137-mediated angiogenesis. Knock-out of CD137 in ApoE-/- mice significantly decreased neovessel density in atherosclerotic plaques. CD137 silencing or inhibition attenuated endothelial cell (ECs) proliferation, migration, and tube formation. We found activation of CD137 signaling for increased VEGFR2 transcription and translation steadily. Moreover, CD137 signaling activated phosphorylated VEGFR2 (Tyr1175) and the downstream Akt/eNOS pathway, whereas neutralizing CD137 signaling weakened the activation of VEGFR2 and the downstream Akt/eNOS pathway. The aortic ring assay further demonstrated that CD137 signaling promoted ECc sprouting. Inhibition of VEGFR2 by siRNA or XL184 (cabozantinib) and inhibition of downstream signaling by LY294002 (inhibits AKT activation) and L-NAME (eNOS inhibitor) remarkably abolished proangiogenic effects of CD137 signaling both in vitro and ex vivo. In addition, the condition medium from CD137-activated ECs and vascular endothelial growth factor A (VEGFA) had similar effects on ECs that expressed high VEGFR2. Additionally, activating CD137 signaling promoted endothelial secretion of VEGFA, while blocking CD137 signaling attenuated VEGFA secretion. In conclusion, activation of CD137 signaling promoted sprouting angiogenesis by increased VEGFA secretion and the VEGFR2/Akt/eNOS pathway. These findings provide a basis for stabilizing intraplaque angiogenesis through VEGFR2 intervatioin, as well as cancer treatment via combination of CD137 agonists and specific VEGFR2 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

Zhang

Yin

et al. 2020

Mediators of Inflammation

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“…A previous literature has stated that activation of the PI3K/AKT pathway can modulate migration and angiogenesis in endothelial cells . AKT activation gives rise to microvascular tube formation in endothelial cells, due to the response of VEGF stimulation . Another study has documented that activation of VEGFR2, which can be activated by VEGF, can induce activation of ERK .…”

Section: Discussionmentioning

confidence: 99%

Retracted: lncRNA‐ATB promotes viability, migration, and angiogenesis in human microvascular endothelial cells by sponging microRNA‐195

Zhu

Sun²,

Ma³

et al. 2019

J of Cellular Biochemistry

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The atherosclerosis in the arterial system of the extremities is considered as the major pathogenesis of peripheral arterial disease. The present work aimed to explore the potential role of long noncoding RNA activated by tumor growth factor‐β (lncRNA‐ATB) on the dysfunction of endothelial cells. Human microvascular endothelial cells (HMEC‐1) were transfected with lncRNA‐ATB expressing vectors, and then the formation of tubes and expression of proteins associated with angiogenesis were analyzed using microscope and reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR)/Western blot analysis. Cell viability, migration, and microRNA‐195 (miR‐195) expression were examined by Cell Counting Kit‐8 assay, modified Boyden chambers, Western blot analysis, and RT‐qPCR. The interaction between lncRNA‐ATB and miR‐195 was determined by RT‐qPCR, dual‐luciferase reporter assay, and biotin‐avidin pull‐down assay. Finally, expression of key kinases in the PI3K/AKT and MEK/ERK pathways was determined by Western blot analysis. We found vascular tubulogenesis was induced spontaneously when HMEC‐1 cells were cultured in Matrigel‐coated plates. lncRNA‐ATB overexpression increased cell viability, migration and formation of tubes, along with upregulation of matrix metalloproteinase‐2 (MMP‐2), MMP‐9, and vascular endothelial growth factor. Then, we found lncRNA‐ATB worked as a molecular sponge for miR‐195, and the effects of lncRNA‐ATB on HMEC‐1 cells were reversed by miR‐195 overexpression while were augmented by miR‐195 inhibition. Phosphorylated levels of key kinases in the PI3K/AKT and MEK/ERK pathways were increased by lncRNA‐ATB via miR‐195. In conclusion, lncRNA‐ATB enhanced cell viability, migration and angiogenesis in HMEC‐1 cells through sponging miR‐195. Moreover, the PI3K/AKT and MEK/ERK pathways were activated by lncRNA‐ATB via miR‐195.

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“…There were no obvious changes among the control, CP and Meg3 groups. Under the acute cerebral infarction, the angiogenesis and the endothelial cells migration ability were reduced [28]. MPO brought stronger RBE4 migration ability comparing to the other groups.…”

Section: Mpo Target Rbe4 In Vitro and Down-regulated Meg3 Expressionmentioning

confidence: 82%

Fabrication of a nano polymer wrapping Meg3 ShRNA plasmid for the treatment of cerebral infarction

Shen

Zhao

Wang

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Cerebral infarction is with poorer prognosis and high rates of mortality. After cerebral infarction, the promoting angiogenesis can accelerate the recovery of neurological function. Long non-coding RNA (LncRNA) maternally expressed gene 3 (Meg3) was overexpressed in cerebral infarction area and the knockdown of Meg3 promotes neovascularization and improves nerve function. In this study, we fabricated a nano-polymer wrapped Meg3 short hairpin RNA (ShRNA) plasmid to knockdown Meg3 and conjugated with OX26 antibody (MPO) to realize the brain targeting for the treatment of cerebral infarction. The MPO particle size was 103 ± 11 nm (PDI = 0.27) detected by dynamic light scattering (DLS) and the zeta potential of MPO was -32 mV. MPO achieved brain microvascular endothelial cell (BMEC) targeting and enhanced endothelial cells migration (p < .05), and tube formation (p < .05) in vitro. MPO realized brain tissue target, reduced the volume of cerebral infarction (p < .05) detected by TTC staining, increased capillary density through the HE staining and increased cerebral cortex micro-vessel through immunofluorescence method in vivo. The angiogenesis associated genes Vegfa, and Vegfr2 were upregulated after the treatment of MPO, compared with Meg3 or control plasmid treated group. This study suggested that MPO could achieve brain target and significantly promoted angiogenesis and became a new treatment method for cerebral infarction.

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Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells

Abstract: The present study unveils the pro-angiogenic function and mechanism of soluble DLK1 through activation of Notch1 signaling in endothelial cells.

Cited by 47 publications

References 43 publications

Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway

Retracted: lncRNA‐ATB promotes viability, migration, and angiogenesis in human microvascular endothelial cells by sponging microRNA‐195

Fabrication of a nano polymer wrapping Meg3 ShRNA plasmid for the treatment of cerebral infarction

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