Stepwise arteriovenous fate acquisition during mammalian vasculogenesis

Chong, Diana C.; Koo, Yeon; Xu, Ke; Fu, Stephen; Cleaver, Ondine

doi:10.1002/dvdy.22706

Cited by 111 publications

(165 citation statements)

References 35 publications

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“…We demonstrate that arterial markers including Notch1, ephrin B2 and Cx40 are virtually undetectable at 3-4 ss, when the DA emerges, consistent with a previous report using whole-mount RNA in situ hybridization (Chong et al, 2011). Following this initial stage, a subset of DA ECs gains arterial marker expression, whereas others gain venous marker expression.…”

Section: Developmentsupporting

confidence: 90%

Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals

et al. 2014

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Coordinated arterial-venous differentiation is crucial for vascular development and function. The origin of the cardinal vein (CV) in mammals is unknown, while conflicting theories have been reported in chick and zebrafish. Here, we provide the first molecular characterization of endothelial cells (ECs) expressing venous molecular markers, or venous-fated ECs, within the emergent dorsal aorta (DA). These ECs, expressing the venous molecular markers Coup-TFII and EphB4, cohabited the early DA with ECs expressing the arterial molecular markers ephrin B2, Notch and connexin 40. These mixed ECs in the early DA expressed either the arterial or venous molecular marker, but rarely both. Subsequently, the DA exhibited uniform arterial markers. Real-time imaging of mouse embryos revealed EC movement from the DA to the CV during the stage when venous-fated ECs occupied the DA. We analyzed mutants for EphB4, which encodes a receptor tyrosine kinase for the ephrin B2 ligand, as we hypothesized that ephrin B2/EphB4 signaling may mediate the repulsion of venous-fated ECs from the DA to the CV. Using an EC quantification approach, we discovered that venousfated ECs increased in the DA and decreased in the CV in the mutants, whereas the rest of the ECs in each vessel were unaffected. This result suggests that the venous-fated ECs were retained in the DA and missing in the CV in the EphB4 mutant, and thus that ephrin B2/EphB4 signaling normally functions to clear venous-fated ECs from the DA to the CV by cell repulsion. Therefore, our cellular and molecular evidence suggests that the DA harbors venous progenitors that move to participate in CV formation, and that ephrin B2/EphB4 signaling regulates this aortic contribution to the mammalian CV.

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Section: Developmentsupporting

confidence: 90%

Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals

et al. 2014

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“…S2A). To distinguish AEC and venous endothelial cell (VEC) populations, we performed hierarchical clustering and principal component analysis with a set of arterial and venous markers (16). Among the five cell populations classified (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of human pluripotent stem cell-derived arterial endothelial cells

Zhang

Chu

Hou

et al. 2017

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

111

106

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Here, we report the derivation of arterial endothelial cells from human pluripotent stem cells that exhibit arterial-specific functions in vitro and in vivo. We combine single-cell RNA sequencing of embryonic mouse endothelial cells with an EFNB2-tdTomato/ EPHB4-EGFP dual reporter human embryonic stem cell line to identify factors that regulate arterial endothelial cell specification. The resulting xeno-free protocol produces cells with gene expression profiles, oxygen consumption rates, nitric oxide production levels, shear stress responses, and TNFα-induced leukocyte adhesion rates characteristic of arterial endothelial cells. Arterial endothelial cells were robustly generated from multiple human embryonic and induced pluripotent stem cell lines and have potential applications for both disease modeling and regenerative medicine.arterial endothelial cells | arterial-specific functions | myocardial infarction | single-cell RNA-seq | human pluripotent stem cell differentiation

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“…Ligand binding to the Notch receptor releases the Notch intracellular domain (NICD), which translocates to the nucleus and forms a transcriptional activation complex with the otherwise repressive DNA-bound Rbpj [CSL, Su(H)] (Bray, 2006). Combined ablation of Notch1 and Notch4, which are both principally expressed in arterial endothelial cells during early vascular remodelling (Chong et al, 2011;Jahnsen et al, 2015), results in severe vascular remodelling defects (Krebs et al, 2000), as does ablation of the Notch downstream effector Rbpj or of Dll4, a Notch ligand specific within the vasculature to arteries (Duarte et al, 2004;Gale et al, 2004;Krebs et al, 2004). However, loss of Notch signalling does not fully recapitulate the arterial defects downstream of Vegfa ablation (Carmeliet et al, 1996;Krebs et al, 2000;Lawson et al, 2002), and the arterially restricted gene expression patterns of components of the Notch pathway do not fully overlap with activated Vegfa (Lawson, 2003), suggesting that additional factors are involved in the regulation of Notch-mediated arterial fate.…”

mentioning

confidence: 99%

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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Stepwise arteriovenous fate acquisition during mammalian vasculogenesis

Cited by 111 publications

References 35 publications

Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals

Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals

Functional characterization of human pluripotent stem cell-derived arterial endothelial cells

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

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