Published online before print March 22, 2007, doi: 10.1161/01.RES.0000265065.26744.17
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© 2007 American Heart Association, Inc.
Molecular Medicine |
Dicer Dependent MicroRNAs Regulate Gene Expression and Functions in Human Endothelial Cells
From the Department of Pathology (Y.S., J.S.P.), Department of Pharmacology (C.F.-H., W.C.S.), Yale University School of Medicine, New Haven, Conn.
Correspondence to William C. Sessa, Boyer Center for Molecular Medicine, Room 436, Yale University School of Medicine, New Haven, CT 06536. E-mail william.sessa{at}yale.edu
Dicer is a key enzyme involved in the maturation of microRNAS (miRNAs). miRNAs have been shown to be regulators of gene expression participating in the control of a wide range of physiological pathways. To assess the role of Dicer and consequently the importance of miRNAs in the biology and functions of human endothelial cells (EC) during angiogenesis, we globally reduced miRNAs in ECs by specific silencing Dicer using siRNA and examined the effects on EC phenotypes in vitro. The knockdown of Dicer in ECs altered the expression (mRNA and/or protein) of several key regulators of endothelial biology and angiogenesis, such as TEK/Tie-2, KDR/VEGFR2, Tie-1, endothelial nitric oxide synthase and IL-8. Although, Dicer knockdown increased activation of the endothelial nitric oxide synthase pathway it reduced proliferation and cord formation of EC in vitro. The miRNA expression profile of EC revealed 25 highly expressed miRNAs in human EC and using miRNA mimicry, miR-222/221 regulates endothelial nitric oxide synthase protein levels after Dicer silencing. Collectively, these results indicate that maintenance and regulation of endogenous miRNA levels via Dicer mediated processing is critical for EC gene expression and functions in vitro.
Key Words: endothelium • Dicer • miRNA • angiogenesis
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