Endothelial Cell Fate Determination: A Top Notch Job in Vascular Decision-Making

Naiche, L.A.; Villa, Stephanie R.; Kitajewski, Jan

doi:10.1101/cshperspect.a041183

Cited by 7 publications

(4 citation statements)

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“…The Notch pathway regulates angiogenesis in almost all steps with different downstream effectors. 10 For instance, Notch activation by FSS upregulates GJA4, which increases the expression of p27 to induce cell-cycle arrest and EC arterialization. 15 We recently identified a panel of miRNAs that mediate the action of Notch signaling in regulating EC proliferation, migration, and sprouting.…”

Section: Discussionmentioning

confidence: 99%

“…The Notch signaling pathway, which is composed of Notch receptors (Notch1-4), Notch ligands (Delta-like [Dll] 1, 3, 4; Jagged [Jag] 1, 2) on neighboring cells, and the downstream transcription factor recombination signal binding protein Jκ (RBPj) in mammals, plays a central role in regulating arteriovenous specification during embryonic development. 10 , 11 Notch activation cell-autonomously promotes EC arterialization by inducing the expression of arterial genes, 12 , 13 and a lack of Notch signaling leads to the increased expression of venous genes in arterial areas. 14 Notably, Notch1 was recently identified as a mechanotransduction sensor of blood flow-derived shear stress in vessel ECs, and shear stress-triggered Notch activation enhances barrier function by upregulating gap junction proteins, such as GJA4, suppressing EC proliferation, and promoting arterial specification.…”

Section: Introductionmentioning

confidence: 99%

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miR-342-5p downstream to Notch enhances arterialization of endothelial cells in response to shear stress by repressing MYC

Zhang¹,

Sun²,

Zhang³

et al. 2023

Molecular Therapy - Nucleic Acids

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-342-5p downstream to Notch enhances arterialization of endothelial cells in response to shear stress by repressing MYC

Zhang¹,

Sun²,

Zhang³

et al. 2023

Molecular Therapy - Nucleic Acids

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“…Diabetes can in uence NOTCH signaling through several mechanisms: Chronic high blood sugar levels can lead to the glycation of proteins and lipids, potentially modifying NOTCH receptors and their ligands, which could alter their function and disrupt normal signaling. Increased oxidative stress in diabetes can damage cellular components, including NOTCH pathway proteins, potentially altering their function and leading to aberrant signaling [59]. The pro-in ammatory milieu commonly associated with diabetes can modulate NOTCH signaling, either enhancing or inhibiting the pathway in ways that disrupt normal cellular responses.…”

Section: Notch Signaling Transcription Factors Diabetes-induced Disru...mentioning

confidence: 99%

Diabetes-Induced Vascular Dysfunction and Stemness Decline Investigated via Transcription Factor-Driven Genetic Switches

Shafi,

Irfan,

Ahmed

et al. 2024

Preprint

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Background: Diabetes mellitus precipitates cardiovascular complications through hyperglycemia, oxidative stress, and inflammation, disrupting vascular cell function. This dysfunction involves altered regulation of transcription factors like Nrf2 and FOXP1, leading to endothelial dysfunction, impaired angiogenesis, and faulty vascular remodeling. Additionally, diabetes reduces the stemness of vascular progenitor cells, hampering vascular repair and homeostasis. Understanding these mechanisms is crucial for identifying therapeutic targets to mitigate diabetic vascular complications.Methods: Databases, including PubMed, MEDLINE, Google Scholar, and open access/subscription-based journals were searched for published articles without any date restrictions, to investigate the diabetes-induced vascular dysfunction and stemness decline through the lens of vascular transcription factor-driven genetic switches. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate how diabetes harms vascular cells. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).Results: This study reveals significant dysregulation of key transcription factors including Nrf2, FOXP1, SMAD, PAX3/7, and GATA in diabetes, leading to compromised oxidative stress responses and increased inflammatory signaling in vascular cells. In endothelial cells, impaired function of these factors resulted in decreased nitric oxide production and increased endothelial permeability. Additionally, altered FOXP1 and GATA activity exacerbated vascular inflammation. In VSMCs, diabetes-induced transcription factor dysregulation promoted a shift from a contractile to a synthetic phenotype, characterized by increased proliferation and matrix production, contributing to vascular stiffness and atherosclerosis. The stemness of vascular progenitor cells was notably reduced, affecting their differentiation capabilities and exacerbating vascular complications in diabetic conditions.Conclusion: Diabetes impairs vascular health by disrupting key transcription factors and signaling pathways, leading to endothelial dysfunction, abnormal vascular remodeling, and a decline in stemness of vascular cells. Dysregulated factors like Nrf2, FOXP1, and GATA contribute to reduced nitric oxide production, increased vascular permeability, and enhanced inflammation, exacerbating atherosclerosis and hypertension. Addressing these dysfunctions through targeted therapies that enhance transcription factor activity and modulate signaling pathways may mitigate diabetes-related vascular complications. Further research is essential for developing effective interventions to restore vascular homeostasis in diabetic patients.

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“…Under hypoxia, VEGFA (and possibly other angiogenic factors) is released in the hypoxic tissue, guiding endothelial cells (ECs) to the ischemic site to restore blood flow and oxygen availability. Once attracted, ECs compete for the tip position, a dynamic process guided by the Notch signaling pathway and affected by hypoxia ( Figure 1 ) ( Naito et al, 2020 ; Naiche et al, 2022 ). Additionally, EC survival under hypoxia is stimulated through autocrine VEGFA signaling, although it does not significantly affect angiogenesis ( Lee et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

Oliveira,

Annex,

Popel

2024

Front. Physiol.

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Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis.Methods: We calibrate and fit the model parameters based on well-established modeling techniques that include structural and practical parameter identifiability, uncertainty quantification, and global sensitivity.Results: Our results indicate that the main pathways involved in patterning tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia interferes with how different stimuli affect patterning. Additionally, our simulations indicate that Notch signaling might regulate vascular permeability and establish different Nitric Oxide release patterns for tip/stalk cells. Following simulations with various stimuli, our model suggests that factors such as time under hypoxia and oxygen availability must be considered for EC pattern control.Discussion: This project provides insights into the signaling and patterning of endothelial cells under various oxygen levels and stimulation by VEGFA and is our first integrative approach toward achieving EC control as a method for improving angiogenesis. Overall, our model provides a computational framework that can be built on to test angiogenesis-related therapies by modulation of different pathways, such as the Notch pathway.

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Endothelial Cell Fate Determination: A Top Notch Job in Vascular Decision-Making

Cited by 7 publications

References 0 publications

miR-342-5p downstream to Notch enhances arterialization of endothelial cells in response to shear stress by repressing MYC

miR-342-5p downstream to Notch enhances arterialization of endothelial cells in response to shear stress by repressing MYC

Diabetes-Induced Vascular Dysfunction and Stemness Decline Investigated via Transcription Factor-Driven Genetic Switches

Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

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