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Published online before print April 10, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070951

Accepted for publication February 5, 2008.

Article

The Benefit of Docosahexanoic Acid on the Migration of Vascular Smooth Muscle Cells Is Partially Dependent on Notch Regulation of MMP-2/-9

Sandrine Delbosc, Martine Glorian, Anne-Sophie Le Port, Gilbert Béréziat, Marise Andréani, and Isabelle Limon@

From Physiologie et Physiopathologie, Université Pierre et Marie Curie, Paris Cedex, France

@ To whom correspondence should be addressed. E-mail: isabelle.limon{at}snv.jussieu.fr.


  Abstract

The Notch pathway is involved in the regulation of the migratory/proliferative phenotype acquired by vascular smooth muscle cells (VSMCs) in the pro-inflammatory context of vascular diseases. Here, we investigated whether docosahexaenoic acid (DHA), a polyunsaturated, {omega}-3 fatty acid, could reduce fibrinolytic/matrix-metalloproteinase (MMP) activity and whether this reduction occurs through the modulation of Notch signaling. Rat VSMCs were transdifferentiated with interleukin-1{beta} and then treated with DHA. Migration/proliferation was determined by performing a wound healing assay and measuring MMP-2/-9 activity, type 1 plasminogen activator inhibitor levels, and the expression of these proteins. The involvement of Notch in regulating the fibrinolytic/MMP system was evidenced using Notch pathway inhibitors and the forced expression of Notch1 and Notch3 intracellular domains. DHA significantly decreased VSMC migration/proliferation induced by interleukin-1{beta} as well as fibrinolytic/MMP activity. Prevention of Notch1 target gene transcription enhanced the interleukin-1{beta} effects on MMPs and on migration, whereas Notch3 intracellular domain overexpression reduced these effects. Finally, DHA increased Notch3 expression, Hes-1 transcription (a Notch target gene), and enhanced {gamma}-secretase complex activity. These results suggest that inhibition of the Notch pathway participates in the transition of VSMCs toward a migratory phenotype. These results also suggest that the beneficial inhibitory effects of DHA on fibrinolytic/MMP activity are related in part to the effects of DHA on the expression of Notch pathway components, providing new insight into the mechanisms by which {omega}-3 fatty acids prevent cardiovascular diseases.






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Copyright © 2008 by the American Society for Investigative Pathology.