Notch1 and Notch3 coordinate for pericyte-induced stabilization of vasculature

Tefft, Juliann B; Bays, Jennifer; Lammers, Alex; Kim, Sudong; Eyckmans, Jeroen; Chen, Christopher

doi:10.1152/ajpcell.00320.2021

Cited by 24 publications

(29 citation statements)

References 59 publications

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“…Notch1 expression was increased at 2 weeks postirradiation. It is worth noting that by performing single-cell RNA-seq analysis of brain tissues from RIBI patients (Figure S4C), we confirmed that Notch3 expression was most abundant in the mural cells (including VSMCs and pericytes), as previously reported, 27 and less detected in the endothelial cells. We next used Pdgfrb -Cre; Ai9 mice to verified the specific expression of Notch3 in the tdTomato-positive mural cells in the brains of irradiated and control mice (Figure 4C).…”

Section: Resultssupporting

confidence: 88%

Notch Signaling Mediates Radiation-Induced Smooth Muscle Cell Hypermuscularization and Cerebral Vasculopathy

Yang

et al. 2022

Stroke

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Background: Emerging evidence highlighted vascular injury in aggravating radiation-induced brain injury (RIBI), a common complication of radiotherapy. This study aimed to delineate the pathological feature of cerebral small vessel and investigate the functional roles of Notch signaling in RIBI. Methods: Brain tissue and functional MRI from RIBI patients were collected and analyzed for radiation-induced vasculopathy. A RIBI mouse model was induced by a single dose of 30-Gy cranial irradiation. Vascular morphology, pulsatility, and reactivity to pharmacological interventions, such as nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, were monitored by 2-photon imaging in mice at 6 weeks postirradiation. Western blot, real-time quantitative PCR, immunofluorescence staining, and behavioral tests were performed. The effect of N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester, a Notch inhibitor, was used to investigate the vascular pathogenesis of RIBI mouse model. Results: Morphologically, radiation resulted in vascular malformation featured by focal contractile rings together with general stenosis. Functionally, radiation also led to hypoperfusion, attenuated vascular pulsatility, and decreased dilation to nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid. Mechanically, Notch activation and increased expression of α-SMA protein were found in both surgical specimens of RIBI patients and the irradiated mice. Importantly, Notch inhibition by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester significantly alleviated cerebral hypoperfusion, vasculopathy, and cognitive deficits in the RIBI mouse model. Conclusions: Radiation-induced cerebral vasculopathy showed bead-like shape and increased contractile state. Inhibition of Notch signaling by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester effectively attenuated vasculopathy and relieved cognitive impairment, suggesting Notch signaling as a therapeutic target for the treatment of RIBI.

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Section: Resultssupporting

confidence: 88%

Notch Signaling Mediates Radiation-Induced Smooth Muscle Cell Hypermuscularization and Cerebral Vasculopathy

Yang

et al. 2022

Stroke

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“…The contemporary increase of Jag1 and LFng that is induced by Bmp9, together with the anti-angiogenic role of Bmp9, thus appear counterintuitive. Jag1 plays a crucial role for the signaling crosstalk of ECs with pericytes (Liu, Kennard and Lilly, 2009; Tefft et al ., 2022), fundamental for endothelial stabilization (Geevarghese and Herman, 2014; Dibble et al ., 2023). Therefore, to reconcile Bmp9-mediated LFng and Jag1 upregulation, we investigated whether LFng plays a role in this context.…”

Section: Resultsmentioning

confidence: 99%

“…Motivated by previous experiments (Benedito et al ., 2009; Larrivée et al ., 2012; Kakuda and Haltiwanger, 2017; Kakuda et al ., 2020; Tefft et al ., 2022), we extended our ODE model of EC signaling by adding the EC crosstalk with pericytes as mediated by Jag1 (Fig. 5A).…”

Section: Resultsmentioning

confidence: 99%

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

Ristori,

Thuret,

Hooker

et al. 2023

Preprint

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SummaryIn briefThe mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates the crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby regulating the endothelial cell behavior and temporal dynamics of their identity during sprouting angiogenesis.HighlightsBmp9 upregulates the expression of LFng in endothelial cells.LFng regulates the temporal dynamics of tip/stalk selection and rearrangement.LFng indicated to play a role in hereditary hemorrhagic telangiectasia.Bmp9 and LFng mediate the endothelial cell-pericyte crosstalk.Bone Morphogenic Protein 9 (Bmp9), whose signaling through Activin receptor-like kinase 1 (Alk1) is involved in several diseases, has been shown to independently activate Notch target genes in an additive fashion with canonical Notch signaling. Here, by integrating predictive computational modeling validated with experiments, we uncover that Bmp9 upregulates Lunatic Fringe (LFng) in endothelial cells (ECs), and thereby also regulates Notch activity in an inter-dependent, multiplicative fashion. Specifically, the Bmp9-upregulated LFng enhances Notch receptor activity creating a much stronger effect when Dll4 ligands are also present. During sprouting, this LFng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement. Our results further indicate that LFng can play a role in Bmp9-related diseases and in pericyte-driven vessel stabilization, since we find LFng contributes to Jag1 upregulation in Bmp9-stimulated ECs; thus, Bmp9-upregulated LFng results in not only enhanced EC Dll4-Notch1 activation, but also Jag1-Notch3 activation in pericytes.

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“…Differences in the role of pericytes on barrier function in these microvessels may result from differences in cell sources, seeding arrangements, shear stress magnitude, and lumen diameter. Recently, Tefft et al (47) used a microvessel model with human brain vascular pericytes and human neonatal dermal blood microvascular ECs to investigate the signaling pathways involved with pericyte stabilization of the endothelium. Pericyte NOTCH3 and EC NOTCH1 played critical roles in forming stable EC junctions.…”

Section: :1 E220021mentioning

confidence: 99%

“…Recently, Tefft et al . ( 47 ) used a microvessel model with human brain vascular pericytes and human neonatal dermal blood microvascular ECs to investigate the signaling pathways involved with pericyte stabilization of the endothelium. Pericyte NOTCH3 and EC NOTCH1 played critical roles in forming stable EC junctions.…”

Section: Engineered Microvesselsmentioning

confidence: 99%

BEYOND THE ENDOTHELIUM: THE ROLE OF MURAL CELLS IN VASCULAR BIOLOGY: In vitro systems to study endothelial/pericyte cell interactions

Warren

Gerecht

2023

Vascular Biology

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The vasculature is crucial for tissue development and survival, and the stability of blood vessels to perform these functions relies on the interplay between endothelial cells and mural cells. Pericytes are a subtype of mural cells found in the microvasculature that extend their processes to wrap around the endothelial monolayer. Pericytes are recruited during vessel growth through the excretion of soluble factors from endothelial cells where they stabilize angiogenic sprouts and induce maturation of the resident cells. Alterations in these interactions between endothelial cells and pericytes are associated with aberrant vessel growth and disrupted vasculature function characteristic of numerous diseases. Therefore, deeper understanding of the cross-talk between these cell types has numerous implications for understanding morphogenesis and elucidating disease mechanisms. In this review, we highlight recent advances and current trends studying the interactions between endothelial cells and pericytes in vitro. We begin by analyzing 3D hydrogel platforms that mimic the tissue extracellular matrix to investigate signaling pathways and altered vascular function in disease-specific cells. We next examine how microfluidic vasculature-on-a-chip platforms have elucidated the interplay of these vascular cells during angiogenesis and vascular network formation under controlled physiochemical cues and interstitial flow. Additionally, studies have utilized microvessels to measure the effect of shear stress on barrier function through the control of luminal flow and the impact of inflammation on these vascular cell interactions. Finally, we briefly highlight self-assembling human blood vessel organoids, an emerging high-throughput platform to study endothelial cells and pericyte interactions.

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Notch1 and Notch3 coordinate for pericyte-induced stabilization of vasculature

Cited by 24 publications

References 59 publications

Notch Signaling Mediates Radiation-Induced Smooth Muscle Cell Hypermuscularization and Cerebral Vasculopathy

Notch Signaling Mediates Radiation-Induced Smooth Muscle Cell Hypermuscularization and Cerebral Vasculopathy

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

BEYOND THE ENDOTHELIUM: THE ROLE OF MURAL CELLS IN VASCULAR BIOLOGY: In vitro systems to study endothelial/pericyte cell interactions

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