Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance

Nakajima, Hiroyuki; Yamamoto, Kimiko; Agarwala, Sobhika; Terai, Kenta; Fukui, Hajime; Fukuhara, Shigetomo; Ando, Koji; Miyazaki, Takahiro; Yokota, Yasuhiro; Schmelzer, Etienne; Belting, Heinz‐Georg; Affolter, Markus; Lecaudey, Virginie; Mochizuki, Naoki

doi:10.1016/j.devcel.2017.02.019

Cited by 244 publications

(270 citation statements)

References 59 publications

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“…(B) The ox-LDL-treated group had significantly higher miR-496 expression as compared to the control group; ÃÃ P < 0.01 versus PBS; n ¼ 3. Furthermore, they found that adjusting the blood flow to induce nuclear YAP1 translocation in vascular endothelial cells could regulate the expression of filamentous actin and angiomotin, thereby inducing the expression of auxiliary transcription factors (Nakajima et al, 2017). (D) Luciferase reporter assays suggesting that WT miR-496 overexpression in NIH-3T3 cells significantly inhibited the activity of luciferase carrying the Yap1 3 0 UTR sequence.…”

Section: Discussionmentioning

confidence: 99%

Oxidized low‐density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR‐496 expression and inhibiting the Hippo pathway effector YAP

Liu

Zhang

et al. 2019

Cell Biology International

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Oxidized low‐density lipoprotein (ox‐LDL) can damage vascular endothelial cells and cause atherosclerosis, but its epigenetic regulatory mechanism has not been fully elucidated. We show that ox‐LDL induced significant apoptosis and loss of function in human umbilical vascular endothelial cells (HUVECs). At the same time, ox‐LDL significantly decreased the expression of Hippo–YAP/ZAP (Yes‐associated protein/YLP motif–containing 1) pathway proteins as compared to that of the control. The luciferase reporter system confirmed that microRNA (miR)‐496 silenced YAP gene expression by binding to its 3′ untranslated region (3′ UTR). Ox‐LDL–treated miR‐496 overexpression HUVECs had a higher apoptosis rate and more severe dysfunction compared to the control cells. This in‐depth study shows that ox‐LDL inhibits YAP protein expression by inducing miR‐496 expression, leading to its inability to enter the nucleus, thereby losing its function as a transcriptional cofactor for activating the downstream genes. Our findings reveal that, through epigenetic modification, ox‐LDL can inhibit the normal expression of Hippo–YAP/ZAP pathway proteins via miR‐496 expression and induce vascular endothelial cell dysfunction.

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Section: Discussionmentioning

confidence: 99%

Oxidized low‐density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR‐496 expression and inhibiting the Hippo pathway effector YAP

Liu

Zhang

et al. 2019

Cell Biology International

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“…Cancer cells are elusive targets for chemotherapy due to the heterogeneity and genetic instability. However, ECs are genetically stable and have a low mutational rate . The homogeneity, genetic stability, and low mutational rate of ECs provide a low toxicity treatment option without the induction of resistance .…”

Section: Angiogenesis and Antiangiogenesismentioning

confidence: 99%

“…However, ECs are genetically stable and have a low mutational rate. 35 The homogeneity, genetic stability, and low mutational rate of ECs provide a low toxicity treatment option without the induction of resistance. 36 Antiangiogenic agents are considered an ideal treatment of cancers by some and have been investigated both as monotherapies and in combination with traditional drugs.…”

Section: Antiangiogenic Agentsmentioning

confidence: 99%

“…140 Molecular docking indicated that a hybrid of anilinoquinazoline and bis-anilinotriazine could afford potent EphB4 inhibitors. Through such effort, they identified compound (35) as an inhibitor of EphB4 phosphorylation with IC 50 of 0.19 ± 0.07 M. They further exploited this discovery in the design of 3,5-disubstituted anilinopyrimidines as potent EphB4 inhibitors. 141 SAR analysis suggested that 3,5-disubstituted aniline was tolerated at the C-2 position of the pyrimidine ring in compound (35), leading to the identification of a bis-morpholine (36) as potent EphB4 inhibitor with IC 50 of 2.0 nM.…”

Section: Recent Progress In the Development Of Ephb4 Inhibitorsmentioning

confidence: 99%

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New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Shan

Wang

Zhang

2018

Medicinal Research Reviews

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Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.

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“…YAP can be localized in the cytoplasm or translocated to the nucleus, where it associates with TEAD transcription factors 7. Previous studies have shown that various forms of mechanical stimulation, such as substrate stiffness, strain, and shear stress, affected YAP localization by actin fiber remodeling 6, 8, 9, 10. YAP was shown to be involved in the effect of shear stress on ECs and blood vessels,10 however its role in the effect of mechanical strain on vascularization is yet to be established.…”

Section: Introductionmentioning

confidence: 99%

Oscillatory Strain Promotes Vessel Stabilization and Alignment through Fibroblast YAP‐Mediated Mechanosensitivity

2018

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Endothelial cells form the interior layer of blood vessels and, as such, are constantly exposed to shear stress and mechanical strain. While the impact of shear stress on angiogenesis is widely studied, the role of mechanical strain is less understood. To this end, endothelial cells and fibroblasts are cocultured under oscillatory strain to create a vessel network. The two cell types show distinctly different sensitivities to the mechanical stimulation. The fibroblasts, sense the stress directly, and respond by increased alignment, proliferation, differentiation, and migration, facilitated by YAP translocation into the nucleus. In contrast, the endothelial cells form aligned vessels by tracking fibroblast alignment. YAP inhibition in constructs under mechanical strain results in vessel destruction whereas less damage is observed in the YAP‐inhibited static control. Moreover, the mechanical stimulation enhances vessel development and stabilization. Additionally, vessel orientation is preserved upon implantation into a mouse dorsal window chamber and promotes the invading host vessels to orient in the same manner. This study sheds light on the mechanisms by which mechanical strain affects the development of blood vessels within engineered tissues. This can be further utilized to engineer a more organized and stable vasculature suitable for transplantation of engineered grafts.

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Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance

Cited by 244 publications

References 59 publications

Oxidized low‐density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR‐496 expression and inhibiting the Hippo pathway effector YAP

Oxidized low‐density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR‐496 expression and inhibiting the Hippo pathway effector YAP

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Oscillatory Strain Promotes Vessel Stabilization and Alignment through Fibroblast YAP‐Mediated Mechanosensitivity

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