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Endocardial HAND2 orchestrates hypoxic and TGFbeta signaling to modulate coronary artery formation [RNA-Seq]

ABSTRACT: The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent Endo-MT. In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator to regulate endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE311982 | GEO | 2026/05/31

REPOSITORIES: GEO

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Endocardial HAND2 orchestrates hypoxic and TGFbeta signaling to modulate coronary artery formation [CUT&Tag]

Project description:The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent EndoMT. In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 effectively reversed the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint a HAND2-governed endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.

2026-05-31 | GSE311981 | GEO

Endocardial HAND2 orchestrates hypoxic and TGFbeta signaling to modulate coronary artery formation [scRNA-seq]

Project description:The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent Endo-MT. In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator to regulate endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.

2026-05-31 | GSE311983 | GEO

Endocardial HAND2 orchestrates hypoxic and TGFbeta signaling to modulate coronary artery formation

Project description:The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent Endo-MT. In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator to regulate endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.

2026-05-31 | GSE311984 | GEO

Intramyocardial Sprouting Tip Cells Specify Coronary Arterialization

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

Single cell transcriptional profiles of endothelial cells sorted from the hearts with ablation of Wnt/beta-catenin signaling activating cardiomyocytes and without ablation [scRNA-seq]

Project description:To understand how Wnt/β-catenin signaling-activated cardiomyocytes (β-cat ON CMs) promote coronary vessel development, we performed single-cell RNA sequencing of endothelial cells (ECs) sorted from the hearts ablated β-cat ON CMs and those from control hearts, respectively. Our analyses indicated that β-cat ON CMs regulates coronary vessel development by promoting arterialization, a step in the transition of endocardial ECs to coronary ECs.

2024-08-23 | GSE223461 | GEO

Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade

Project description:Coronaries are essential for myocardial growth and heart function. Notch is crucial for mouse embryonic angiogenesis, but its role in coronary development remains uncertain. We show Jag1, Dll4 and activated Notch1 receptor expression in sinus venosus (SV) endocardium. Endocardial Jag1 removal blocks SV capillary sprouting, while Dll4 inactivation stimulates excessive capillary growth, suggesting that ligand antagonism regulates coronary primary plexus formation. Later endothelial ligand removal, or forced expression of Dll4 or the glycosyltransferase MFng, blocks coronary plexus remodeling, arterial differentiation, and perivascular cell maturation. Endocardial deletion of Efnb2 phenocopies the coronary arterial defects of Notch mutants. Angiogenic rescue experiments in ventricular explants, or in primary human endothelial cells, indicate that EphrinB2 is a critical effector of antagonistic Dll4 and Jag1 functions in arterial morphogenesis. Thus, coronary arterial precursors are specified in the SV prior to primary coronary plexus formation and subsequent arterial differentiation depends on a Dll4-Jag1-EphrinB2 signaling cascade.

2019-12-03 | GSE110614 | GEO

Mapping the developing human cardiac endothelium at single cell resolution identifies MECOM as a regulator of arteriovenous identity.

Project description:Aims: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterise the transcriptome of the human fetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart. Methods and Results: We acquired scRNA-seq data of over 10,000 fetal cardiac endothelial cells (EC), revealing divergent EC subtypes including endocardial, capillary, venous, arterial, and lymphatic populations. Gene regulatory network analyses predicted roles for SMAD1 and MECOM in determining the identity of capillary and arterial populations, respectively. Trajectory inference analysis suggested an endocardial contribution to the coronary vasculature and subsequent arterialisation of capillary endothelium accompanied by increasing MECOM expression. Comparative analysis of equivalent data from murine cardiac development demonstrated that transcriptional signatures defining endothelial subpopulations are largely conserved between human and mouse. Furthermore, we revealed that knockdown of MECOM in human embryonic stem cell-derived EC (hESC-EC) resulted in an increase in venous EC marker expression, validating our prediction of its role in arterial EC identity. Conclusions: scRNA-seq of the human fetal cardiac endothelium identified distinct EC populations. A predicted endocardial contribution to the developing coronary vasculature was identified, as well as subsequent arterial specification of capillary EC. Loss of MECOM in hESC-EC increased venous EC marker expression, suggesting a role in maintaining arterial EC identity.

2022-03-02 | GSE195911 | GEO

Single cell evaluation of endocardial HAND2 gene regulatory networks reveals critical HAND2 dependent pathways impacting cardiac morphogenesis.

Project description:The basic-helix-loop-helix transcription factor HAND2 plays a critical role in endocardium to myocardium signaling during cardiac morphogenesis through its role within the NOTCH signaling pathway. Hand2 endocardial deletion (H2CKOs) results in embryonic lethality by E13.5 due to tricuspid atresia (TA) or double inlet left ventricle (DILV) with accompanying intraventricular septum defects, multiple septa, and hypo-trabeculated ventricles. In addition, H2CKOs also exhibit an increased density of coronary lumens. In order to understand the underlying regulatory mechanisms that cause these phenotypes, we undertook a single cell transcriptome analysis of E11.5 H2CKOs hearts.

2023-01-09 | GSE210221 | GEO

Early and extensive venous arterialization during mammalian embryogenesis

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

Transcriptional profiling of purified endocardial and coronary vascular endothelial cells, isolated from murine embryonic hearts, at two developmental stages

Project description:Given that the Nes-gfp allele specifically labels coronary ECs, endogenous GFP and the endomucin marker (which was highly expressed in endocardial cells) were used together to separate endocardial and coronary vascular endothelial cell subpopulations in different developmental stages

2021-02-20 | GSE147117 | GEO

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