VEGF and Notch in Tip and Stalk Cell Selection

Blanco, Raquel; Gerhardt, Holger

doi:10.1101/cshperspect.a006569

Cited by 496 publications

(559 citation statements)

References 107 publications

(177 reference statements)

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“…VEGFR and Notch signaling pathways cooperate closely to specify and balance the differentiation of tip and stalk cells during sprouting 8, 9. Stimulating ECs with VEGFA increases the expression of Notch ligand Dll4.…”

Section: Discussionmentioning

confidence: 99%

“…Stimulating ECs with VEGFA increases the expression of Notch ligand Dll4. In reverse, Notch signaling acts as negative feedback to inhibit the expression of VEGFR2 and VEGFR3 and to increase the VEGFR1 level 9. TGF‐β also attenuates VEGFR2 transcription directly 49.…”

Section: Discussionmentioning

confidence: 99%

“…Notch signal is essential for endothelial sprouting in angiogenesis and the maintenance of vascular homeostasis. Deficiency of RBPJ, the integrative downstream transcription factor of canonical Notch signaling, leads to excessive sprouting and malformation of vessels, whereas activation of Notch signaling restricts angiogenesis 9, 10. The transforming growth factor β (TGF‐β) family of pleiotrophic cytokines, including 3 isoforms of TGF‐β, activins, and bone morphogenetic proteins elicits their biological functions through 5 type 2 receptors, 7 type 1 receptors (also termed activin receptor‐like kinases [ALKs]), and auxiliary receptors endoglin and betaglycan 11.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…С одной стороны, активация HIF-1 в клетках астроглии способствует стимуляции гликолиза и увеличению продукции лактата, который, несомненно, оказывает влияние на функциональную активность клеток церебрального эндотелия и/или транспортируется ими из ткани мозга в кровь. С другой стороны, увеличение активности HIF-1 имеет своим результатом увеличение экспрессии VEGF и активацию Notch-сигнального пути [12], которые регулируют эффективность ангиогенного спрутинга и фенотип так называемых концевых клеток и клеток ствола (tip and stalk cells), формирующих сосуд [13].…”

Section: Introductionunclassified

“…Известно, что VEGF-опосредованная регуляция Notch-сигнальной трансдукции в клетках эндотелия определяет характер активации концевых клеток и клеток ствола (tip and stalk cells и обусловливает про-или антиангиогенную активность, что эффективно контролируется путём применения ингибиторов гамма-секретазы в клетках эндотелия [13]. В целом, в нашей экспериментальной модели мы продемонстрировали, что HIF-1-сопряжённые механизмы регуляции активности клеток астроглиальной и нейрональной природы в развивающемся ГЭБ способствует эффективному барьерогенезу in vitro.…”

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Development of blood-brain barrier under the modulation of HIF activity in astroglial and neuronal cells in vitro

et al. 2016

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Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

et al. 2017

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Phenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well‐studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune evasion, invasion, and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally verified molecular mechanisms and act as ‘hypothesis‐generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive E/M plasticity at both the single‐cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression.

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VEGF and Notch in Tip and Stalk Cell Selection

Cited by 496 publications

References 107 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

Development of blood-brain barrier under the modulation of HIF activity in astroglial and neuronal cells in vitro

Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

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