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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2258.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Impaired Notch4 Activity Elicits Endothelial Cell Activation and Apoptosis

Implication for Transplant Arteriosclerosis

T. Quillard; S. Coupel; F. Coulon; J. Fitau; M. Chatelais; M.C. Cuturi; E. Chiffoleau; B. Charreau

From INSERM, U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation, ITERT, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France.

Correspondence to B. Charreau, INSERM U643, CHU Hôtel Dieu, 30, bd Jean Monnet, 440093 Nantes cedex 01, France. E-mail Beatrice.Charreau{at}univ-nantes.fr

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)β, 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.

Conclusion— Together, our findings indicate that impaired Notch4 activity in graft ECs is a key event associated with TA by triggering EC activation and apoptosis.

Notch pathway controls key functions in vascular cells. Here we report that Notch2, -3, and -4 transcripts are downregulated in transplant arteriosclerosis. Consistently, inflammatory cytokines decrease Notch4 expression and Notch activity in endothelial cells. Notch4 or Hes1 knockdown promotes endothelial activation and apoptosis, both events that contribute to transplant arteriosclerosis pathogenesis.

Key Words: transplant arteriosclerosis • notch • endothelial cells • activation • apoptosis