Disruption of the transcription factor recombination signal-binding protein-Jκ (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice

Wang, Lin; Wang, Chunmei; Hou, Lihong; Dou, Guo‐Rui; Wang, Yao-Chun; Hu, Xingbin; He, Fangping; Feng, Fan; Zhang, Hongwei; Liang, Yingmin; Dou, Kefeng; Han, Hua

doi:10.1002/hep.22579

Cited by 50 publications

(62 citation statements)

References 32 publications

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“…Primary murine liver sinusoid endothelial cells were isolated using a recommended protocol32 from 3 pairs of NICD ECA and control mice. MiRNA expression profiling by small RNA sequencing and data analysis were conducted by a commercial service (RiboBio).…”

Section: Methodsmentioning

confidence: 99%

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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BackgroundEndothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.Methods and ResultsSmall RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential.ConclusionsmiR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.

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Section: Methodsmentioning

confidence: 99%

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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“…Immunohistochemistry analysis for CD31, vascular endothelial growth factor receptor 2, and Hif1α in tissues was performed as previously described (35). Microvessels labeled by CD31 and vascular endothelial growth factor receptor 2 (VEGFR2) were counted.…”

Section: Elisa and Immunohistochemistrymentioning

confidence: 99%

Notch Signaling Determines the M1 versus M2 Polarization of Macrophages in Antitumor Immune Responses

et al. 2010

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Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch signaling showed TAM phenotypes. Forced activation of Notch signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J-mediated Notch signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch signaling. Cancer Res; 70(12); 4840-9. ©2010 AACR.

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“…We report vessel enlargement or entanglement in adult uterus and gastrointestinal tract, but not in adult brain. Previous studies have shown that global deletion of Rbpj from adult mice leads to increased EC proliferation (Dou et al, 2008;Li et al, 2012;Wang et al, 2009) and vascular anomalies resembling veno-occlusive disease of the liver ) and aortic valve disease . Despite effects on the endothelium and vasculature, (not significant); N=42 controls, N=29 mutants.…”

Section: Rbpj Is Required In Postnatal Endothelium To Prevent Avmsmentioning

confidence: 99%

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

et al. 2014

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Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification by promoting arterial, as opposed to venous, endothelial cell (EC) fate. To understand the essential role of endothelial Notch signaling in postnatal AV organization, we used inducible Cre-loxP recombination to delete Rbpj, a mediator of canonical Notch signaling, from postnatal ECs in mice. Deletion of endothelial Rbpj from birth resulted in features of AVMs by P14, including abnormal AV shunting and tortuous vessels in the brain, intestine and heart. We further analyzed brain AVMs, as they pose particular health risks. Consistent with AVM pathology, we found cerebral hemorrhage, hypoxia and necrosis, and neurological deficits. AV shunts originated from capillaries (and possibly venules), with the earliest detectable morphological abnormalities in AV connections by P8. Prior to AV shunt formation, alterations in EC gene expression were detected, including decreased Efnb2 and increased Pai1, which encodes a downstream effector of TGFβ signaling. After AV shunts had formed, whole-mount immunostaining showed decreased Efnb2 and increased Ephb4 expression within AV shunts, suggesting that ECs were reprogrammed from arterial to venous identity. Deletion of Rbpj from adult ECs led to tortuosities in gastrointestinal, uterine and skin vascular beds, but had mild effects in the brain. Our results demonstrate a temporal requirement for Rbpj in postnatal ECs to maintain proper artery, capillary and vein organization and to prevent abnormal AV shunting and AVM pathogenesis.

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Disruption of the transcription factor recombination signal-binding protein-Jκ (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice

Cited by 50 publications

References 32 publications

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Notch Signaling Determines the M1 versus M2 Polarization of Macrophages in Antitumor Immune Responses

Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

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