Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

Holderfield, Matthew; Hughes, Christopher C.W.

doi:10.1161/circresaha.107.167171

Cited by 290 publications

(243 citation statements)

References 147 publications

(241 reference statements)

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“…These steps are consistent with seminal observations of in vivo angiogenesis showing the emergence of tip cells from an existing vessel, and stalk cells that establish apical/basal polarity and form a lumen that excludes the tip cell (24,25,41). VEGF has been shown to be important in triggering such tip cells to extend thin, actin-rich protrusions and in guiding stalk cells to form elongated multicellular sprouts (5,25).…”

Section: Discussionsupporting

confidence: 88%

Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro

Nguyen

Stapleton²,

Yang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

449

441

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Angiogenesis is a complex morphogenetic process whereby endothelial cells from existing vessels invade as multicellular sprouts to form new vessels. Here, we have engineered a unique organotypic model of angiogenic sprouting and neovessel formation that originates from preformed artificial vessels fully encapsulated within a 3D extracellular matrix. Using this model, we screened the effects of angiogenic factors and identified two distinct cocktails that promoted robust multicellular endothelial sprouting. The angiogenic sprouts in our system exhibited hallmark structural features of in vivo angiogenesis, including directed invasion of leading cells that developed filopodia-like protrusions characteristic of tip cells, following stalk cells exhibiting apical-basal polarity, and lumens and branches connecting back to the parent vessels. Ultimately, sprouts bridged between preformed channels and formed perfusable neovessels. Using this model, we investigated the effects of angiogenic inhibitors on sprouting morphogenesis. Interestingly, the ability of VEGF receptor 2 inhibition to antagonize filopodia formation in tip cells was context-dependent, suggesting a mechanism by which vessels might be able to toggle between VEGF-dependent and VEGFindependent modes of angiogenesis. Like VEGF, sphingosine-1-phosphate also seemed to exert its proangiogenic effects by stimulating directional filopodial extension, whereas matrix metalloproteinase inhibitors prevented sprout extension but had no impact on filopodial formation. Together, these results demonstrate an in vitro 3D biomimetic model that reconstitutes the morphogenetic steps of angiogenic sprouting and highlight the potential utility of the model to elucidate the molecular mechanisms that coordinate the complex series of events involved in neovascularization.A ngiogenesis, the process by which new capillary vessels sprout from existing vasculature, plays a critical role in embryonic development and wound healing, and its dysregulation can contribute to cancer progression as well as numerous inflammatory and ischemic diseases (1, 2). Consequently, therapeutic strategies to suppress, enhance, or normalize angiogenesis are widely sought to treat a broad spectrum of diseases (1, 2). The most mature among these approaches targets the activity of angiogenic growth factors, such as vascular endothelial growth factor (VEGF), to modulate relevant signaling pathways and control the angiogenesis process. Indeed, inhibitors of such pathways have emerged as a mainstay therapy for some cancers and diabetic retinopathy (3-5). However, it is still unclear how the endothelial cells (ECs) lining blood vessels form new vessels, or how angiogenic factors regulate such a dynamic, multicellular process.Examining the physical process of angiogenesis requires experimental systems in which the formation of new capillary vessels can be easily observed and manipulated. Commonly used in vivo models such as the mouse dorsal window chamber, chick chorioallantoic membrane, and mouse corneal micro...

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Section: Discussionsupporting

confidence: 88%

Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro

Nguyen

Stapleton²,

Yang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

449

441

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“…53 EC sprouting has been explained by a model in which TGF-β synergizes with VEGF and Notch to drive migration, partly through induction of ID1, required for EC migration. 54 The link between the p53 family members and TGF-β signaling in somatic cells has been previously established and it has been suggested, but never addressed, that the p53 homologs might interact with TGF-β in development. 24 In this work we show that the absence of p73 results in a significant decrease in TGF-β1 and ID1 levels in all the models analyzed.…”

Section: Discussionmentioning

confidence: 99%

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-β and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

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“…In addition, TGF‐β signaling is also the major signal driving EndMT through the major transcription factors Snail and Slug,5 which are also modulated by Notch and other pathways 22, 23. Although each of these signaling pathways is essential for vascular development, coordinated regulation of ECs through signaling pathway interactions guarantees normal vascular morphogenesis and homeostasis 24. Nevertheless, how these signals crosstalk remains unclear.…”

Section: Introductionmentioning

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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Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

Cited by 290 publications

References 147 publications

Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro

Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ 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

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