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Updated: Jun 30, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Impaired Notch4 activity elicits endothelial cell activation and apoptosis: implication for transplant
T Quillard1, S Coupel, F Coulon
1INSERM U643, Nantes, F44000 France.
Insights
Impaired Notch4 signaling in cardiac allografts promotes transplant arteriosclerosis (TA) by activating endothelial cells (ECs) and causing apoptosis. Restoring Notch4 activity is crucial for EC survival and repair.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- The Notch signaling pathway regulates critical vascular and endothelial cell (EC) functions.
- The role of Notch in allografted vessels and transplant arteriosclerosis (TA) remains largely unknown.
Purpose of the Study:
- To investigate Notch pathway regulation in cardiac allograft arteriosclerosis.
- To examine the implication of Notch signaling in EC dysfunction during TA.
Main Methods:
- Analysis of Notch receptor transcript levels in TA versus control allografts.
- Assessment of tumor necrosis factor (TNF), TGF-beta, and IL10 effects on Notch4 expression in vitro and in vivo.
- Evaluation of Notch inhibition (reduced CBF1 activity, Hes1 expression) and Notch4/Hes1 knockdown effects on ECs.
Main Results:
- Notch2, -3, and -4 transcript levels were downregulated in TA.
- TNF, TGF-beta, and IL10 correlated with decreased Notch4 expression.
- Notch inhibition and Notch4/Hes1 knockdown enhanced vascular cell adhesion molecule-1 expression, promoted EC apoptosis, and impaired endothelial repair.
Conclusions:
- Impaired Notch4 activity in graft ECs is a key event in TA.
- This impairment triggers EC activation and apoptosis, contributing to disease development.
Objective:
Notch signaling pathway controls key functions in vascular and endothelial cells (EC). However, little is known about the role of Notch in allografted vessels during the development of transplant arteriosclerosis (TA). This study investigated regulation of the Notch pathway on cardiac allograft arteriosclerosis and further examined its implication in EC dysfunction.
Methods And Results:
Here we show that, among Notch receptors, Notch2, -3, and -4 transcript levels were markedly downregulated in TA compared to tolerant and syngeneic allografts. TA correlates with high levels of tumor necrosis factor (TNF), transforming growth factor (TGF)beta, and IL10, which consistently decrease Notch4 expression in transplants and cultured ECs. We found that inhibition of Notch activity, reflected by both a reduced CBF1 activity and Hes1 expression, parallels the downregulation of Notch4 expression mediated by TNF in ECs. Notch4 and Hes1 knockdown enhances vascular cell adhesion molecule-1 expression and promotes EC apoptosis. Silencing Notch4 or Hes1 also drastically inhibits repair of endothelial injury. Overall, our results suggest that Notch4 and basal Notch activity are required to maintain EC quiescence and for optimal survival and repair in response to injury.
Conclusions:
Together, our findings indicate that impaired Notch4 activity in graft ECs is a key event associated with TA by triggering EC activation and apoptosis.
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