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Incongruence between transcriptional and vascular pathophysiological cell states II

ABSTRACT: The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or the ligand Dll4 dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch, inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTor, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes, and related pathophysiology. Our findings also suggest that vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE231612 | GEO | 2023/05/12

REPOSITORIES: GEO

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Incongruence between transcriptional and vascular pathophysiological cell states I

Project description:The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or the ligand Dll4 induces angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTor, had no effect on the vascular expansion induced by Dll4 loss, however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes, and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.

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ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning

Project description:Precise vascular patterning is critical for normal growth and development. The ERG transcription factor drives Delta like ligand 4 (DLL4)/Notch signalling and is thought to act as pivotal regulators of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC specific Focal Adhesion Kinase (FAK)-knockout (KO) and point-mutant FAK-knockin mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins identified that endothelial nuclear-FAK interacts with the de-ubiquitinase USP9x and the ubiquitin ligase TRIM25 enzymes. Further in silico analysis corroborates that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x.

2022-07-05 | PXD033447 | Pride

Hypoxia-induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling

Project description:Hypoxia (low oxygen) and Notch signaling are two important regulators of vascular development, but how they interact in controlling the choice between arterial and venous fates for endothelial cells during vasculogenesis is less well understood. In this report, we show that hypoxia and Notch signaling intersect in promotion of arterial differentiation. Hypoxia upregulated expression of the Notch ligand Dll4 and increases Notch signaling, in a process requiring the vasoactive hormone adrenomedullin but not endogenous VEGF. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, functional Notch signaling was required for hypoxia to upregulate the arterial marker genes Depp, connexin40 (Gja5), Cxcr4 and Hey1. In conclusion, the data reveal an intricate interaction between hypoxia and Notch signaling in the control of endothelial cell differentiation, including a hypoxia/adrenomedullin/Dll4 axis that initiates Notch signaling and a requirement for Notch signaling to effectuate hypoxiamediated induction of the arterial differentiation program. 12 microarray samples consisting of >50,000 FACS sorted CD31+ cells purified from wild type mouse CCE ES cells that were differentiated into the endothelial lineages in 3 biological replicates. The ES cells were subjected to embryoid body formation over 4 days in hanging drop cultures, FACS sorted for Flk1 positive vascular progenitors cells and plated for a further 4 days in normoxia (21% oxygen) or hypoxia (1.5-2% oxygen) with or without 4 umol/l gamma-secretase inhibitor L-685.458.

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Dll4iDEC mouse liver endothelial cells

Project description:Myc and its target Odc1 were among the most 250 strongly upregulated genes in Dll4 mutant ECs, compared with Notch1 and Rbpj mutants. Myc is known to activate important ribosome biogenesis and protein translation pathways, favoring cell growth. Dll4iDEC livers showed upregulation of a large range of canonical E2F, Myc, and mTORC1 target genes and ribosomal genes, particularly in the activated, proliferating, and endothelial tip-cell clusters. This hypermetabolic transcriptional status was confirmed by in-depth proteomics analysis of protein lysates obtained from freshly isolated liver ECs, providing the first proteomics analysis of the endothelial tip-cell state induced by targeting Dll4.

2023-04-11 | PXD041349 | Pride

Hypoxia-induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling

2013-02-08 | GSE35894 | GEO

Deubiquitinase USP10 regulates Notch signaling in the endothelium

Project description:Notch signaling is critical for vascular morphogenesis by co-determining the sprouting behavior of endothelial cells. Here, we investigate the function of ubiquitin-specific peptidase 10 (USP10) in regulation of the turnover of the NOTCH1 intracellular domain. HUVEC were transfected with scrambled or USP10 targeting siRNA and then stimulated by treatment with DLL4 or control. RNA for analysis was isolated after 24 hours of DLL4 stimulation.

2019-04-26 | E-MTAB-7774 | biostudies-arrayexpress

MicroRNA expression in HMVECs: control vs. VEGF-treated vs. PEDF/VEGF-treated

Project description:MicroRNA expression profiling of human microvascular endothelial cells (HMVECs) treated with either vascular endothelial growth factor (VEGF) only or in combination with the natural angiogenesis inhibitor pigment epithelial-derived factor (PEDF). Originally we were interested in the microRNA-mediated regulation of angiogenesis by the endogenous anti-angiogenic PEDF. To identify the microRNAs involved in PEDF signaling in activated endothelial cells, we compared the levels of microRNAs in non-treated microvascular endothelial cells, cells treated with VEGF, and cells treated with a combination of VEGF and PEDF. After treatment, total RNA content was isolated and sent for analysis to LC Sciences, LLC. They performed expression profiling and completed statistical analysis, based on which we confirmed the regulation of one of the microRNAs, mir-27b. In the following experiments, we identified the targets of mir-27b relevant for angiogenesis and confirmed our findings in zebrafish and mouse models. The manuscript describes the key role of mir-27b in determination of the endothelial tip cell fate and venous differentiation by regulating Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). Three-condition experiment: untreated (control) HMVECs vs. VEGF-treated HMVECs vs. PEDF/VEGF-treated HMVECs.

2011-12-31 | E-GEOD-34735 | biostudies-arrayexpress

Vascular niche induction of hematopoietic progenitors from pluripotent stem cells

Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines Â± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines Â± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence. Transcriptome sequencing of Macaca nemestrina (Mn) iPSCs

2015-12-31 | E-GEOD-64644 | biostudies-arrayexpress

Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins

Project description:Vascular morphogenesis requires a delicate gradient of Notch signaling that is controlled, at least in part, by the distribution of ligands (Dll4 and Jagged1). How jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here we showed that Jag1 mRNA is a direct target of zinc finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we found robustly induced by VEGF. Endothelial cells lacking ZFP36 displayed high levels of JAG1 and increased angiogenic sprouting in vitro. Similarly, mice lackingZfp36in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front altered NOTCH1 signaling, increasing the number of tip cells; a phenotype that was rescued by imposing haploinsufficiency ofJag1. Our findings reveal an important feedforward loop, whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.

2023-12-04 | GSE235462 | 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.

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