Impaired Notch4 Activity Elicits Endothelial Cell Activation and Apoptosis

Quillard, Thibaut; Coupel, Stéphanie; Coulon, Flora; Fitau, Juliette; Chatelais, Mathias; Cuturi, Maria‐Cristina; Chiffoleau, Elise; Charreau, Béatrice

doi:10.1161/atvbaha.108.174995

Cited by 57 publications

(63 citation statements)

References 36 publications

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“…For example, it has been shown that impaired Notch4 activity in graft endothelium of transplant atherosclerosis results in vascular cell adhesion molecule-1 expression and endothelial cell apoptosis. 27 The increased inflammation observed in our mutants might represent the outcome of diminished Notch function both in macrophages and endothelium, with the effect that the endothelial phenotype is dominant.…”

Section: Notch Mutant Valve Tissue Displays Hallmarks Of Cavdmentioning

confidence: 87%

Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL

Nus

MacGrogan

Martínez‐Poveda

et al. 2011

ATVB

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Objective— Calcific aortic valve disease is similar to atherosclerosis in that both diseases result from chronic inflammation and endothelial dysfunction. Heterozygous NOTCH1 mutations have been associated to calcific aortic disease and a bicuspid aortic valve. We investigated whether mice with genetic inactivation of the Notch signaling pathway are prone to develop valve disease when exposed to a predisposing diet. Methods and Results— Using Doppler echocardiography, histology, immunohistochemistry, quantitative gene expression analysis, and cell culture assays, we examined the effect of a hypercholesterolemic diet supplemented with vitamin D on mice heterozygous for null mutations in the Notch1 receptor or the effector transcription factor gene RBPJk . After 16 weeks on the hyperlipidemic diet, calcific aortic disease was detected in heterozygous RBPJk mice. Analysis of valve leaflets revealed macrophage infiltration, enhanced collagen deposition, proosteogenic protein expression, and calcification. Heterozygous null Notch1 mice displayed milder histopathologic changes and did not develop any significant hemodynamic disturbance. Valvular disease correlated with reduced expression of the Notch target gene Hey1 in valves of RBPJk heterozygous mice fed the hyperlipidemic diet. Consistent with the in vivo data, Notch signaling inhibition in porcine valve interstitial cells led to downregulation of HEY1 transcription, activation of osteogenic markers, and increased calcified nodule formation. Conclusion— We show that Notch signaling disruption via RBPJk heterozygous inactivation results in aortic valve disease. Notch1 heterozygous mice do not show functional impairment, suggesting that additional Notch receptors may be involved in aortic valve homeostasis and disease. Our data establish a genetic mouse model of calcific aortic valve disease and may help to identify a patient population with reduced valvular NOTCH signaling at risk for developing this disease.

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Section: Notch Mutant Valve Tissue Displays Hallmarks Of Cavdmentioning

confidence: 87%

Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL

Nus

MacGrogan

Martínez‐Poveda

et al. 2011

ATVB

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“…Notch-4 in arterial endothelial cells enhances the expression of VCAM-1 in the absence or presence of a pro-inflammatory stimulus (51). Furthermore, Notch-1 induces the expression of VCAM-1 by endothelial cells in the absence of inflammatory cytokines and potentiates the IL1␤-dependent VCAM-1 upregulation by interacting with the NF-kB pathway (52).…”

Section: Egfl7 Regulates Endothelial Activation During Inflammationmentioning

confidence: 99%

Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation

Pinte

Caetano

Bras

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerActivation of the blood vessel endothelium is a critical step during inflammation. Endothelial cells stimulated by pro-inflammatory cytokines play an essential part in the adhesion and extravasation of circulating leukocytes into inflamed tissues. The endothelial egfl7 gene (VE-statin) represses endothelial cell activation in tumors, and prior observations suggested that it could also participate in the regulation of endothelial cell activation during inflammation. We show here that Egfl7 expression is strongly repressed in mouse lung endothelial cells during LPS-and TNF␣-induced inflammation in vivo. LPS have a limited effect on Egfl7 expression by endothelial cells in vitro, whereas the pro-inflammatory cytokine TNF␣ strongly represses Egfl7 expression in endothelial cells. TNF␣ regulates the egfl7 gene promoter through regions located between ؊7585 and ؊5550 bp ahead of the main transcription start site and via an NF-B-dependent mechanism. Conversely, Egfl7 regulates the response of endothelial cells to TNF␣ by restraining the induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, resulting in a decreased adhesion of leukocytes onto endothelial cells stimulated by TNF␣. Egfl7 regulates the expression of these adhesion molecules through the NF-B and MEK/Erk pathways, in particular by preventing the proteasomemediated degradation of IkB␣ both in non-activated endothelial cells and during activation. Egfl7 is thus an endogenous and constitutive repressor of blood vessel endothelial cell activation in normal and inflammatory conditions and participates in a loop of regulation of activation of these cells by pro-inflammatory cytokines.Endothelial cells line the luminal side of blood vessels in direct contact with the circulation. Under normal conditions, the endothelium forms a non-adhesive and non-thrombogenic surface on which blood cells slide with minimal interactions with the vascular wall. During inflammation, endothelial cells become activated in response to pro-inflammatory cytokines, which promote a strong increase in the expression levels of leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1), 4 and vascular cell adhesion molecule-1 (VCAM-1). These adhesion molecules are expressed at the endothelial cell surface and participate in the rolling, arrest, firm adhesion, and extravasation of immune cells from the circulation through the endothelium and toward the tissues (1). Endothelial cell activation in response to inflammation and its subsequent capture of leukocytes is thus a vital response, and its regulation is critical. Excessive or aberrant local activation of endothelial cells leads to inflammatory disorders such as atherosclerosis, chronic inflammation, multiple sclerosis, and rheumatoid arthritis. Activation of the endothelium is transitory, and endothelial cells resume a basal, nonactivated condition when pro-inflammatory cytokines levels recess. Thus, most of the ...

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“…No significant change in Notch1 was observed. Down-regulation of Notch4 was mainly driven by the graft's ECs [88]. In cultured ECs, Notch4 exhibited an anti-inflammatory function by reducing the TNF-mediated induction of vascular cell adhesion molecule-1 (VCAM-1) that plays a crucial role in the recruitment of immune cells to inflammatory sites [88].…”

Section: The Notch Pathwaymentioning

confidence: 99%

Signaling of endothelial cytoprotection in transplantation

Charreau

2012

Human Immunology

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Impaired Notch4 Activity Elicits Endothelial Cell Activation and Apoptosis

Cited by 57 publications

References 36 publications

Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL

Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL

Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation

Signaling of endothelial cytoprotection in transplantation

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