Cyclic strain regulates the Notch/CBF-1 signaling pathway in endothelial cells: role in angiogenic activity.

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.