Eph-ephrin signaling couples endothelial cell sorting and arterial specification
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223738 | GEO | 2024/01/30
REPOSITORIES: GEO
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Project description:Eph-ephrin signaling couples endothelial cell sorting and arterial specification
| PRJNA928081 | ENA
Project description:Dilated cardiomyopathy is a frequently occurring human disease compromising heart function and a major cause of cardiac death. The causes of cardiomyopathies are often unknown. There is increasing evidence indicating that endothelial cells lining blood vessels control the homeostasis of various organs, but the special properties and functional roles of the vasculature in the adult heart maintain remain little understood. Here, we have used mouse genetics, imaging and cell biology approaches to investigate how vascular homeostasis in the adult heart is controlled by EphB4 and its ligand ephrin-B2, which are known regulators of sprouting angiogenesis, vascular morphogenesis and arteriovenous differentiation during development. We show that inducible and endothelial cell-specific inactivation of the Ephb4 gene in adult mice is compatible with survival, but leads to rupturing of cardiac capillaries, cardiomyocyte hypertrophy, and pathological cardiac remodelling. In contrast, EphB4 is not required for the integrity and homeostatic function of capillaries in skeletal muscle. Our analysis of mutant mice and cultured endothelial cells shows that EphB4 controls the function of caveolae, cell-cell adhesion under mechanical stress and lipid transport. Together, our findings establish that EphB4 maintains critical functional properties of the adult cardiac vasculature and thereby prevents dilated cardiomyopathy-like defects.
2019-11-20 | PXD012575 | Pride
Project description:Distinct endothelial cell cycle states (early G1 vs. late G1) provide different “windows of opportunity” to enable the differential expression of genes that regulate venous and arterial specification, respectively. Endothelial cell cycle control and arterial-venous identities are disrupted in vascular malformations including arteriovenous (AV) shunts which is a hallmark of hereditary hemorrhagic telangiectasia (HHT). We show how endothelial cell late G1 arrest induced by Palbociclib modulates the expression of genes regulating arterio-venous identity and prevents AVM development induced by BMP9/10 inhibition.
2023-12-31 | GSE245197 | GEO
Project description:EPHrin receptors (EPH) are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates the intracellular kinase activity. EPHs are key players in bidirectional intercellular signalling, controlling cell morphology, adhesion and migration. They are increasingly recognized as cancer drug targets. We analysed the binding of the patented Novartis inhibitor NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples were regioisomers NVPiso with a single methyl group binding to an adjacent nitrogen atom compared to the patented compound. The two compounds of identical mass reveal different binding modes. Further, both, in vitro and in vivo experiments show that the isomers differ in their kinase affinity and selectivity.
2018-09-05 | PXD009188 | Pride
Project description:The heterogeneity of embryonic endothelial cells (ECs) especially the distinction of arteriovenous ECs remains incompletely characterized. We established a mouse single-EC transcriptomic landscape at mid-to-late gestation stage and identified 19 subclusters, including Etv2+Bnip3+ early ECs and 2 specialized ECs. Most of these subtypes were grouped by their vascular-bed types, while ECs from brain, heart and liver were grouped by their tissue origins. Unlike arterial ECs (aECs), embryonic venous (vECs) and capillary ECs (cECs) shared less markers with their adult counterparts. Notably, capillary clusters showed some venous characteristics and one of them served as an intermediate state of arteriovenous specification. Compared to the more early stage, a clear arteriovenous branch which also going through a venous plexus was identified. aECs and vECs showed distinct transcriptional modules including specific regulatory networks of transcription factors. Especially, USF1 and MECOM were verified functioning in arteriovenous differentiation through human induced pluripotent stem cells (hiPSC) differentiation models. We therefore provide a new map of endothelial heterogeneity highlighting regulation of arteriovenous specification.
2024-01-25 | GSE247450 | GEO
Project description:The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart. Single-cell transcriptomics were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. We discovered that a tip-cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life. We also identified non-overlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways, suggesting that differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.
2024-07-25 | GSE223266 | GEO
Project description:The cellular evolutions and molecular programs underlying the arteriovenous fate settling of embryonic vascular endothelial cells (ECs) are critical for understanding arteriogenesis and inspiring new approaches for regenerative biology. Using different strategies of single-cell RNA sequencing, we constructed the transcriptional landscape of early arteriovenous EC development in both mouse and human embryos, demonstrating the evolutionary conservation of principal vascular EC types and providing a series of conserved arteriovenous genes. We showed an unexpected diversity of arteriovenous characteristics in morphologically alike vascular plexus and further uncovered two transcriptomically distinct arterial EC types, whereas most of heterologous ligand-receptor pairs were shared by different arterial vasculatures. By computational predicting and further genetic lineage tracing, we revealed the widespread venous arterialization in the mid-gestational mouse embryo proper. Interestingly, we demonstrated at transcriptomic level that Notch1 was dispensable for venous arterialization but required subsequently for the arterial feature strengthening in the arterial plexus ECs. Altogether, our findings unprecedentedly detail the comprehensive single-cell mapping of early embryonic vascular ECs in vivo, decipher an asymmetric arteriovenous characteristics different than that in adults, and reveal an extensive venous-to-arterial fate conversion in the vascular plexus.
2022-01-26 | GSE94877 | GEO
Project description:Arteries are thought to be formed through the induction of a highly conserved arterial genetic programme in a subset of vessels that will later experience an increase in oxygenated blood flow. The initial steps of arterial specification require both VEGF and Notch signalling. Here, we combined inducible genetic mosaics and transcriptomics to modulate and define the function of these signalling pathways in cell proliferation, arteriovenous (AV) differentiation and mobilization. We observed that endothelial cells (ECs) with high VEGF or Notch signalling are intrinsically biased to mobilize and form arteries; nevertheless, they are not genetically pre-determined, and can also form veins. Mechanistically, we found that higher VEGF and Notch signalling in pre-arterial capillaries suppresses Myc-dependent metabolic and cell-cycle activities, promoting the incorporation of ECs in arteries. Mosaic lineage tracing studies revealed that ECs completely lacking the Notch-Rbpj transcriptional activator complex rarely form arteries; however, these cells regained the ability to form arteries when Myc function was suppressed. Thus, arterial development does not require the direct induction of a Notch-dependent arterial differentiation programme, but rather the timely suppression of endothelial cell-cycle progression and metabolism, a process preceding arterial mobilization and complete differentiation.
2020-09-30 | GSE158731 | GEO
Project description:Endothelial cells (EC) lining arteries and veins have distinct molecular and functional signatures. The (epi)genetic regulatory mechanisms underlying this heterogeneity in human EC are incompletely understood. Using genome-wide microarray screening we established a specific fingerprint of freshly isolated arterial (HUAEC) and venous EC (HUVEC) from human umbilical cord comprising 64 arterial and 12 venous genes, representing distinct functions and pathways. Among the arterial genes were 8 transcription factors, including HEY2, a downstream target of Notch signaling and the current ‘golden standard’ pathway for arterial EC specification. Short-term culture of HUAEC or HUVEC abrogated differential gene expression resulting in a default state. Erasure of arterial gene expression was at least in part due to loss of canonical Notch activity and HEY2 expression. Notably, nCounter analysis revealed that restoring HEY2 expression or Delta-like 4 (Dll4)-induced Notch signaling in cultured HUVEC or HUAEC only partially reinstated the arterial EC gene signature while combined overexpression of the 8 transcription factors restored this fingerprint much more robustly. Each transcription factor had a different impact on gene regulation, with some stimulating only few and others boosting a large proportion of arterial genes. Interestingly, although there was some overlap and cross-regulation, the transcription factors largely complemented each other in regulating the arterial EC gene profile. Thus, our study showed that Notch signaling determines only part of the arterial EC signature and identified additional novel and complementary transcriptional players in the complex regulation of human arteriovenous EC identity To identify an arteriovenous (AV) fingerprint in human endothelial cells (EC) across different vascular beds, we used microarrays on RNA from 38 EC samples corresponding to 6 cultured human arterial-EC types (hepatic artery EC or HHAEC, N=3; aorta EC or HAEC, N=2; coronary artery EC or HCAEC, N=2; iliac artery EC or HIAEC, N=2; pulmonary artery EC or HPAEC, N=3; and umbilical artery EC or HUAEC-C, N=5), 4 cultured human venous-EC types (hepatic vein EC or HHVEC, N=3; iliac vein EC or HIVEC, N=3; pulmonary vein EC or HPVEC, N=2; and umbilical vein EC or HUVEC-C, N=5), freshly isolated HUAEC (HUAEC-F, N=4) and freshly isolated HUVEC (HUVEC-F, N=4). Due to the difficulty to obtain biopsies from healthy donors, we did not have access to freshly isolated aEC or vEC matched for all cultured EC types.
2014-01-07 | E-GEOD-43475 | biostudies-arrayexpress
Project description:Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying retinal vascular development in Cdh5-CreERT2;R26FUCCI2aR reporter mice, we found that venous and arterial endothelial cells are in distinct cell cycle states during development and in adulthood. That is, venous endothelial cells reside in early G1 state, while arterial endothelial cells reside in late G1 state. Single cell RNA sequencing of developing retinal endothelial cells revealed that BMP signaling and early G1 state are enriched in venous endothelial cells, while TGF-b signaling and late G1 state are enriched in arterial endothelial cells. Cultured endothelial cells in early vs. late G1 exhibited significant differences in gene expression and activity, especially among BMP/TGF-b signaling components. The early G1 state was found to be essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-b1-induced arterial gene expression. In a mouse model of endothelial cell hyperproliferation and disrupted arterial-venous specification, pharmacological inhibition of endothelial cell cycle prevented the vascular defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.
2022-08-22 | GSE169039 | GEO