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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1289.)
© 2007 American Heart Association, Inc.

Vascular Biology

Cyclic Strain Regulates the Notch/CBF-1 Signaling Pathway in Endothelial Cells

Role in Angiogenic Activity

David Morrow; John P. Cullen; Paul A. Cahill; Eileen M. Redmond

From the Department of Surgery (D.M., J.P.C., E.M.R.), University of Rochester Medical Center, Rochester, NY; and the Vascular Health Research Centre (P.A.C.), Dublin City University, Dublin, Ireland.

Correspondence to Dr Eileen M. Redmond, University of Rochester Medical Center, Department of Surgery, Box SURG, 601 Elmwood Avenue, Rochester, NY 14642-8410. E-mail Eileen_Redmond{at}urmc.rochester.edu

Objective— The purpose of this study was to determine the effect of cyclic strain on Notch signaling in endothelial cells.

Methods and Results— Exposure of human endothelial cells (ECs) to cyclic strain (10%) resulted in temporal upregulation of Notch receptors (1 and 4) at the mRNA and protein level. Cyclic strain significantly increased EC network formation on Matrigel (an index of angiogenesis); network AU=775±127 versus 3928±400 for static and strained ECs, respectively. In addition, Angiopoietin 1 (Ang1), Tie1, and Tie2 expression were increased and knockdown of Ang1/Tie1,2 by siRNAs decreased cyclic strain-induced network formation. Knockdown of Notch 1 and 4 by siRNA, or inhibition of Notch mediated CBF-1/RBP-Jk regulated gene expression by RPMS-1, caused a significant decrease in cyclic strain-induced network formation and in Tie1 and Tie2 mRNA expression. Notch 1 or Notch 4 siRNA, but not RPMS-1, inhibited cyclic strain-induced Ang1. Constitutive overexpression of Notch IC resulted in increased network formation, and Ang1 and Tie2 mRNA expression, under both static and strain conditions.

Conclusions— These data suggest that cyclic strain-stimulated EC angiogenesis is mediated in part through a Notch-dependent, Ang1/Tie2 signaling pathway. This pathway may represent a novel therapeutic target for disease states in which hemodynamic force-induced angiogenesis occurs.

A relationship exists between hemodynamic forces and angiogenesis, but details of the signaling involved are scant. We report that cyclic strain stimulates endothelial cell angiogenic activity in vitro, in part, through a Notch-dependent, Angiopoietin1/Tie2 signaling pathway.

Key Words: mechanical forces • Notch • endothelial cells • angiogenesis • angiopoietin

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