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Loss of Jagged1 in mature endothelial cells causes vascular dysfunction with alterations in smooth muscle phenotypes

ABSTRACT: Notch signaling is an evolutionarily conserved pathway that functions via direct cell-cell contact. The Notch ligand Jagged1 (Jag1) has been extensively studied in vascular development, particularly for its role in smooth muscle cell maturation. Endothelial cell-expressed Jag1 is essential for blood vessel formation by signaling to nascent vascular smooth muscle cells and promoting their differentiation. Given the established importance of Jag1 in endothelial cell/smooth muscle crosstalk during development, we sought to determine the extent of this communication in the adult vasculature for blood vessel function and homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE209736 | GEO | 2022/08/01

REPOSITORIES: GEO

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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

Genes regulated/modulated by jagged1 in endothelial cells during inflammation

Project description:Proinflammatory activation of endothelial cells leads to recruitment of leukocytes by upregulation of adhesion molecules and presentation of chemoattractants. In response to such activation there is also a strong shift in the endothelial expression of Notch ligands, with downregulation of Dll4 and a upregulation of JAG1. To assess whether Jagged1 would affect the endothelial activation profile, we suppressed JAG1 expression during IL-1β-induced activation by means of siRNA and performed a genome-wide transcriptome analysis. Our results show for the first time that Jagged1 modulates the transcription profile of activated endothelial cells and describe data that imply a role for Jagged1 in sharpening the inflammatory profile of the vasculature, giving it an edge towards leukocyte recruitment. These findings imply that Jagged1 might be a potential therapeutic target to attenuate inflammation and reduce tissue damage in inflammatory diseases.

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Project description:Objective Notch signaling is re-activated in β cells from obese mice, and is causal to β cell dysfunction. Notch activity is determined in part by expression of transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant β cell dysfunction in obese mice. Methods We assessed expression of Notch pathway components in diet-induced obese (DIO) or leptin receptor-deficient (db/db) mice, and performed single cell RNA sequencing (scRNAseq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, β cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets. Results Jag1 was the only Notch ligand that tracked with increased Notch activity in DIO and db/db mice. Consistently, JAG1 tracked with Notch activity in metabolically inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from DIO and db/db mice potentiated GSIS ex vivo. To demonstrate if β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic mice (β-Jag1TG), which showed impaired glucose intolerance due to reduced GSIS. However, β cell-specific Jagged1 loss-of-function (β-Jag1KO) did not protect against HFD-induced insulin secretory defects or glucose intolerance. Conclusions Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that β cells are not a likely source of the Jagged1 signal.

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Jagged1 regulates miRNA expression profile

Project description:miRNA expression profiles of HMECs treated with 40mM Jagged1 (JAG1) or the control peptide for 1 day Genome-wide miRNA PCR array analysis was performed using human miRNA PCR arrays (MIHS216Z, SABiosceinces) acccording to the manufacturer's instructions

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Active repression of Sox9 by Jag1 is required for silencing the default chondrogenic fate of the vascular smooth muscle wall [set 1]

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