Transcriptional regulators of arterial and venous identity in the developing mammalian embryo

McCracken, Ian R.; Smart, Nicola; Val, Sarah De

doi:10.1016/j.cophys.2023.100691

Cited by 3 publications

(3 citation statements)

References 81 publications

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“…Prior studies of signaling pathways and transcriptional mechanisms that govern arterial and venous specification identified Notch and high VEGFA (vascular endothelial growth factor A) as critical for arterial specification, while BMP signaling and NR2F2 are vital for venous specification. 15,17,20,43,44 This study revealed the transcriptional dynamics of arterial and venous specification and the expression pattern and regulons of TF enriched along aEC and vEC differentiation trajectories. These analyses predicted novel transcriptional regulators of arteriovenous specification.…”

Section: Discussionmentioning

confidence: 85%

Molecular and Spatial Signatures of Mouse Embryonic Endothelial Cells at Single-Cell Resolution

Chen,

Zhang,

DeLaughter

et al. 2024

Circulation Research

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BACKGROUND: Mature endothelial cells (ECs) are heterogeneous, with subtypes defined by tissue origin and position within the vascular bed (ie, artery, capillary, vein, and lymphatic). How this heterogeneity is established during the development of the vascular system, especially arteriovenous specification of ECs, remains incompletely characterized. METHODS: We used droplet-based single-cell RNA sequencing and multiplexed error-robust fluorescence in situ hybridization to define EC and EC progenitor subtypes from E9.5, E12.5, and E15.5 mouse embryos. We used trajectory inference to analyze the specification of arterial ECs (aECs) and venous ECs (vECs) from EC progenitors. Network analysis identified candidate transcriptional regulators of arteriovenous differentiation, which we tested by CRISPR loss of function in human-induced pluripotent stem cells undergoing directed differentiation to arterial or vECs (human-induced pluripotent stem cell-aECs or human-induced pluripotent stem cell-vECs). RESULTS: From the single-cell transcriptomes of 7682 E9.5 to E15.5 ECs, we identified 19 EC subtypes, including Etv2 + Bnip3 + EC progenitors. Spatial transcriptomic analysis of 15 448 ECs provided orthogonal validation of these EC subtypes and established their spatial distribution. Most embryonic ECs were grouped by their vascular-bed types, while ECs from the brain, heart, liver, and lung were grouped by their tissue origins. Arterial ( Eln , Dkk2 , Vegfc , and Egfl8 ), venous ( Fam174b and Clec14a ), and capillary ( Kcne3 ) marker genes were identified. Compared with aECs, embryonic vECs and capillary ECs shared fewer markers than their adult counterparts. Early capillary ECs with venous characteristics as a branch point for differentiation of aEC and vEC lineages. CONCLUSIONS: Our results provide a spatiotemporal map of embryonic EC heterogeneity at single-cell resolution and demonstrate that the diversity of ECs in the embryo arises from both tissue origin and vascular-bed position. Developing aECs and vECs share common venous-featured capillary precursors and are regulated by distinct transcriptional regulatory networks.

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Section: Discussionmentioning

confidence: 85%

Molecular and Spatial Signatures of Mouse Embryonic Endothelial Cells at Single-Cell Resolution

Chen,

Zhang,

DeLaughter

et al. 2024

Circulation Research

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“…The EC layer is the first part of the blood vessel to form, initially via differentiation from mesoderm (vasculogenesis) and later from existing ECs (angiogenesis) 1 . While the first arterial ECs arise during vasculogenesis 2 , single cell transcriptomics and fate mapping experiments spanning humans, mice and zebrafish indicate that most arterial ECs form via angiogenesis from venous and venous-like capillary ECs [3][4][5][6][7][8][9][10][11] . During this process, a subset of ECs reduce cell-cycling and venous gene transcription, induce arterial gene expression and migrate against flow to form into new arteries or extend existing ones.…”

Section: Introductionmentioning

confidence: 99%

“…Although numerous other regulatory pathways have been implicated in arterial transcriptional regulation, their exact contribution has been challenging to establish and none appear essential for arterial EC identity 11 . Both canonical WNT and TGFβ/BMP signalling pathways have been implicated in arterialization yet ECs lacking β-catenin or SMAD4 still express arterial genes and form arterial structures 15,16 .…”

Section: Introductionmentioning

confidence: 99%

A catalogue of verified and characterized arterial enhancers for key arterial identity genes

Nornes,

Bruche,

Adak

et al. 2024

Preprint

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The establishment and growth of the arterial endothelium requires the coordinated expression of numerous genes. However, the transcriptional and signalling pathways regulating this process are still not fully established, and only a small number of enhancers for key arterial genes have been characterized. Here, we sought to generate a useful and accessible cohort of arterial enhancers with which to study arterial transcriptional regulation. We combined in silico analysis with transgenic zebrafish and mouse models to find and validate enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1 and Unc5b). This identified a cohort of enhancers able to independently direct robust transcription to arterial ECs within the vasculature. To elucidate the regulatory pathways upstream of arterial gene transcription, we determined the occurrence of common endothelial transcription factor binding motifs, and assessed direct binding of these factors across all arterial enhancers compared to similar assessments of non-arterial-specific enhancers. These results find that binding of SOXF and ETS factors is a shared event across arterial enhancers, but also commonly occurs at pan-endothelial enhancers. Conversely, RBPJ/Notch, MEF2 and FOX binding was over-represented but not ubiquitous at arterial enhancers. We found no shared or arterial-specific signature for canonical WNT-associated TCF/LEF transcription factors, canonical TGFβ/BMP-associated SMAD1/5 and SMAD2, laminar shear stress-associated KLF factors or venous-enriched NR2F2 factors. This cohort of well characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signalling pathways with arterial gene expression.

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Role of vascular smooth muscle cell clonality in atherosclerosis

Luo,

Fu,

Bell

et al. 2023

Front. Cardiovasc. Med.

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Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. While many cell types contribute to the growing atherosclerotic plaque, the vascular smooth muscle cell (SMC) is a major contributor due in part to its remarkable plasticity and ability to undergo phenotype switching in response to injury. SMCs can migrate into the fibrous cap, presumably stabilizing the plaque, or accumulate within the lesional core, possibly accelerating vascular inflammation. How SMCs expand and react to disease stimuli has been a controversial topic for many decades. While early studies relying on X-chromosome inactivation were inconclusive due to low resolution and sensitivity, recent advances in multi-color lineage tracing models have revitalized the concept that SMCs likely expand in an oligoclonal fashion during atherogenesis. Current efforts are focused on determining whether all SMCs have equal capacity for clonal expansion or if a “stem-like” progenitor cell may exist, and to understand how constituents of the clone decide which phenotype they will ultimately adopt as the disease progresses. Mechanistic studies are also beginning to dissect the processes which confer cells with their overall survival advantage, test whether these properties are attributable to intrinsic features of the expanding clone, and define the role of cross-talk between proliferating SMCs and other plaque constituents such as neighboring macrophages. In this review, we aim to summarize the historical perspectives on SMC clonality, highlight unanswered questions, and identify translational issues which may need to be considered as therapeutics directed against SMC clonality are developed as a novel approach to targeting atherosclerosis.

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Transcriptional regulators of arterial and venous identity in the developing mammalian embryo

Cited by 3 publications

References 81 publications

Molecular and Spatial Signatures of Mouse Embryonic Endothelial Cells at Single-Cell Resolution

Molecular and Spatial Signatures of Mouse Embryonic Endothelial Cells at Single-Cell Resolution

A catalogue of verified and characterized arterial enhancers for key arterial identity genes

Role of vascular smooth muscle cell clonality in atherosclerosis

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