Notch Pathway Targets Proangiogenic Regulator Sox17 to Restrict Angiogenesis

Lee, Seung Hun; Lee, Sungsu; Yang, Hanseul; Song, Sukhyun; Kim, Kangsan; Saunders, Thomas L.; Yoon, Jong‐Hwan; Koh, Gou Young; Kim, Injune

doi:10.1161/circresaha.115.303142

Cited by 84 publications

(71 citation statements)

References 48 publications

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“…Strain-specific variations in mice after depletion of individual SoxF genes and varying levels of compensation from other SoxF factors have resulted in some contradictory reports (Corada et al, 2013;Lee et al, 2014), as is also the case for zebrafish morphant analysis (Cermenati et al, 2008;Herpers et al, 2008;Pendeville et al, 2008). Nonetheless, the results described here agree with an increasingly convincing body of work suggesting that SoxF factors influence Notch signalling yet are unaffected by Notch ablation.…”

Section: Discussionsupporting

confidence: 73%

“…By contrast, the ablation of Notch signalling in the vasculature does not significantly impact the expression of SoxF (Abdelilah et al, 1996;Corada et al, 2013). Different experimental models have positioned SoxF genes both upstream (Corada et al, 2013) and downstream (Lee et al, 2014) of Notch signalling in endothelial cells, suggesting a complex relationship between these two pathways.…”

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confidence: 99%

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SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

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Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role in this biological process, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SOXF binding sites clearly established a requirement for members of the SOXF group of transcription factors (SOX7,-17 and-18) to drive these enhancers activity in vivo. Further, endogenous deletion of the notch1b enhancer led to a significant augmentation of arterio-venous defects in notch-pathway deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for the activity of NOTCH1 and notch1b enhancers, and for correct endogenous Notch1 gene transcription. These findings therefore position SOXF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

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“…For excising Sox7 and Sox17 in endothelial cells after birth, Cdh5(BAC)-CreER T2 driver line was bred with Sox7 fl/fl and Sox17 flfl mice, respectively, and their progeny were subcutaneously administered with tamoxifen as described. 11 For compound haploinsufficiency of Sox7 and Sox17, Sox7 mCh/+ mice were crossed with Sox17 GFP/+ mice.…”

Section: Mutant Micementioning

confidence: 99%

“…Sox17 8,9 and Sox18 10 are known to be indispensable for arterial and lymphatic differentiation, respectively, in mice. Sox17 has additional roles in sprouting angiogenesis during development 11 and artery maintenance in adulthood. 12 However, the vascular role of Sox7 is just beginning to be understood in mammalian vascular development, 13 although the compound silencing of Sox7 and Sox18 and the Sox7 genetic targeting have been reported to induce defective arterial differentiation in zebrafish.…”

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confidence: 99%

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

Kim

Yang

et al. 2016

Circulation Research

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Rationale: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. Objective:

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“…[11][12][13] The transcription factor Sox17 is an essential player in vascular development through the regulation of angiogenesis 14 and arterial differentiation.…”

Section: Clinical Perspective On P 1005mentioning

confidence: 99%

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

et al. 2015

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Intracranial aneurysm (IA), which is characterized by the ballooning of an intracerebral artery, is a common vascular abnormality, with a prevalence of 2% to 5% in the general population, and frequently leads to vascular rupture with high mortality.1,2 IA is considered to be influenced by various acquired and inherited factors. [3][4][5] Although IA incidence is associated with several acquired risk factors, including smoking and hypertension, 6-9 its genetic factors are poorly understood, and the generation of reliable disease models to recapitulate its pathogenesis has therefore been difficult. Current treatment of IA depends largely on surgical clipping or endovascular coiling without any therapeutic drug administration. 10 Clinical Perspective on p 1005In recent attempts to reveal genetic factors related to IA, a series of genome-wide association studies based on a large population of patients with IA suggested a few susceptible candidate loci, including Sox17. [11][12][13] The transcription factor Sox17 is an essential player in vascular development through the regulation of angiogenesis 14 and arterial differentiation. 15Although Sox17 plays a crucial role in tumor angiogenesis, 16 the relationship between Sox17 and other vascular abnormalities, including IA, during adulthood has not yet been studied. Because IA pathology has focused on vascular walls rather than on endothelial layers, how Sox17, which is specifically expressed in endothelial cells, is involved in IA formation remains to be explored. To address a potential link between IA formation and Sox17, we investigated the vascular changes in intracerebral arteries of a Sox17 loss-of-function mouse model. MethodsAn expanded Methods section can be found in the online-only Data Supplement.Background-Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. Methods and Results-The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings. Conclusions-Our findings demonstrate that Vascular Corrosion Casting and Scanning Electron MicroscopyMi...

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Notch Pathway Targets Proangiogenic Regulator Sox17 to Restrict Angiogenesis

Cited by 84 publications

References 48 publications

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial Aneurysm

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