Publisher Correction: High mitogenic stimulation arrests angiogenesis

Pontes, Samuel; Fernández-Chacón, Macarena; Luo, Wen; Lunella, Federica Francesca; Casquero-García, Verónica; García-González, Irene; Hermoso, Ana; Rocha, Susana; Bansal, Mayank; Benedito, Rui

doi:10.1038/s41467-019-10474-9

Cited by 4 publications

(23 citation statements)

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“…In the case of ECs, the increase in Notch transcriptional activity is usually associated with a decrease in the cell´s activity and the adoption of stalk-cell features in the case of the angiogenic front, or the adoption of arterial cell features in the case of remodeling or mature vessels. This is confirmed by the fact that loss of Dll4/Notch1/Rbpj induces a significant increase in the number of sprouting cells (tip cells) and a loss of arterial identity [ 1 , 6 , 29 , 31 , 67 , 68 , 74 – 80 ].…”

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 85%

“…Mechanistically, the suppression of endothelial sprouting by higher Dll4-Notch activity was initially thought to depend on the repression of VEGFR-2 transcription [ 31 ], a phenomena mostly observed in human umbilical vein ECs (HUVECs) under NOTCH overactivation [ 68 , 81 , 82 ]. However, several recent studies in zebrafish and mice have shown that physiological Notch signaling does not regulate Vegfr2 transcription, translation, or phosphorylation in vivo [ 6 , 77 , 79 , 83 ]. In contrast to Vegfr2 , the transcription of the homologous Vegfr3 receptor [ 80 , 83 ] or its protein levels [ 77 ] were significantly upregulated after loss of Notch signaling in vivo, and thought to be sufficient to induce EC sprouting [ 61 , 62 ].…”

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 99%

“…Despite the controversy surrounding the mechanistic cross-talk between Notch and VEGFR signaling, it is clear from several recent studies conducted in zebrafish and mice that Notch suppresses the downstream MAPK/ERK signaling [ 6 , 64 ], by yet unidentified mechanisms and independently of decreases in Vegfr2 signaling [ 6 ]. This observation is in line with the fact that stalk cells have significantly more Notch and less ERK activity than tip cells.…”

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 99%

“…Tgf-beta/Bmp/Alk signaling and its mechanistic interaction with Notch and Nrp1 also seem to be highly relevant for tip–stalk-cell differentiation [ 94 ]. All these studies, however, have not clearly addressed the paradoxical evidence, showing that stalk cells have significantly lower VEGF/ERK activity, even though they proliferate more than tip cells [ 6 , 55 ].…”

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 99%

“…Besides a simplistic positive or negative role of specific molecular mechanisms on angiogenesis, it is also becoming clear that certain molecular mechanisms may have important roles only in some vascular development and disease contexts, and their effect is dose-dependent. Mechanisms that at low functional doses promote angiogenesis may be inhibitory at high doses and vice versa [ 6 , 8 ]. Also, genes that can induce quiescence and vascular maturation when growth factor bioavailability is low or blood flow increases may be essential to sustain active angiogenesis when the vascular niche is high on growth factors and blood perfusion is lower.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Mühleder

Fernández-Chacón

García-González

et al. 2020

Cell. Mol. Life Sci.

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Therapeutic modulation of vascular cell proliferation and migration is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The general view is that an increase in vascular growth factor levels or mitogenic stimulation is beneficial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprouting. However, several recent studies showed that an increase in mitogenic stimuli can also lead to the arrest of angiogenesis. This is due to the existence of intrinsic signaling feedback loops and cell cycle checkpoints that work in synchrony to maintain a balance between endothelial proliferation and sprouting. This balance is tightly and effectively regulated during tissue growth and is often deregulated or impaired in disease. Most therapeutic strategies used so far to promote vascular growth simply increase mitogenic stimuli, without taking into account its deleterious effects on this balance and on vascular cells. Here, we review the main findings on the mechanisms controlling physiological vascular sprouting, proliferation, and senescence and how those mechanisms are often deregulated in acquired or congenital cardiovascular disease leading to a diverse range of pathologies. We also discuss alternative approaches to increase the effectiveness of pro-angiogenic therapies in cardiovascular regenerative medicine.

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Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 85%

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 99%

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 99%

Section: Key Regulators Of Endothelial Sproutingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Mühleder

Fernández-Chacón

García-González

et al. 2020

Cell. Mol. Life Sci.

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Automated in vivo compound screening with zebrafish and the discovery and validation of PD 81,723 as a novel angiogenesis inhibitor

Mauro

Turgeon

Gupta

et al. 2022

Sci Rep

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Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.

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Fate and state transitions during human blood vessel organoid development

Nikolova

Wimmer

et al. 2022

Preprint

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Blood vessel organoids (BVOs) derived from human pluripotent stem cells have emerged as a novel system to understand human vascular development, model disorders, and develop regenerative therapies. However, it is unclear which molecular states constitute BVOs and how cells differentiate and self-organize within BVOs in vitro and after transplantation. Here we reconstruct BVO development over a time course using single-cell transcriptomics. We observe progenitor states that bifurcate into endothelial and mural fates, and find that BVOs do not acquire definitive arterio-venous endothelial identities in vitro. Chromatin accessibility profiling identifies gene regulatory network (GRN) features associated with endothelial and mural fate decisions, and transcriptome-coupled lineage recording reveals multipotent progenitor states within BVOs. We perform single-cell genetic perturbations within mosaic BVOs to dissect the impact of transcription factor (TF) and receptor depletion on cell differentiation, and highlight multiple TFs including MECOM and ETV2 as strong-effect regulators of human BVO development. We show that manipulation of VEGF and Notch signaling pathways alters BVO morphogenesis and endothelial GRNs, and induces arteriovenous-like state differentiation. We analyze matured BVOs after transplantation using scRNA-seq, and observe matured endothelium with clear arteriovenous specification. We also observe off-target cell fates with bone and adipocyte features, suggesting multipotent states reside within the BVOs in vitro that expand and diversify in less restrictive conditions. Finally, we map vascular disease associated genes to BVO cell states to highlight the potential of BVOs for disease modeling. Altogether, our data and analyses provide the first comprehensive cell state atlas of BVO development and illuminate both the power and limitation of BVOs for translational research.

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Publisher Correction: High mitogenic stimulation arrests angiogenesis

Abstract: The original version of this Article contained errors in Fig. 8. In panel a, the labels 'VEGF', 'Notch', 'p21', and 'P-ERK' were inadvertently omitted. This has been corrected in the PDF and HTML versions of the Article.

Cited by 4 publications

References 0 publications

Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Automated in vivo compound screening with zebrafish and the discovery and validation of PD 81,723 as a novel angiogenesis inhibitor

Fate and state transitions during human blood vessel organoid development

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