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.


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.
Morrow
David
D
University of Rochester Medical Center, Department of Surgery, 601 Elmwood Avenue, Rochester, NY 14642-8410, USA.
Cullen
John P
JP
Cahill
Paul A
PA
Redmond
Eileen M
EM
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011673:Pulsatile Flow; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D000074562:Receptor, Notch4; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497761:NOTCH1 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; C497570:RBPJ protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2