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Functional interplay between endothelial nitric oxide synthase and membrane type 1–matrix metalloproteinase in migrating endothelial cells

AuthorsGenís, Laura; Gonzalo, Pilar; Tutor, Antonio S. ; Gálvez, Beatriz G.; Martínez-Ruiz, Antonio ; Zaragoza, Carlos; Lamas Peláez, Santiago ; Tryggvason, Kral; Apte, Suneel S.; Arroyo, Alicia G.
Keywordsmembrane type 1–matrix metalloproteinase (MT1-MMP)
EC migration
Issue Date15-Oct-2007
PublisherAmerican Society of Hematology
CitationBlood 110:2916-2923 (2007)
AbstractNitric oxide (NO) is essential for vascular homeostasis and is also a critical modulator of angiogenesis; however, the molecular mechanisms of NO action during angiogenesis remain elusive. We have investigated the potential relationship between NO and membrane type 1–matrix metalloproteinase (MT1-MMP) during endothelial migration and capillary tube formation. Endothelial NO synthase (eNOS) colocalizes with MT1-MMP at motility-associated structures in migratory human endothelial cells (ECs); moreover, NO is produced at these structures and is released into the medium during EC migration. We have therefore addressed 2 questions: (1) the putative regulation of MT1-MMP by NO in migratory ECs; and (2) the requirement for MT1-MMP in NO-induced EC migration and tube formation. NO upregulates MT1-MMP membrane clustering on migratory human ECs, and this is accompanied by increased degradation of type I collagen substrate. MT1-MMP membrane expression and localization are impaired in lung ECs from eNOS-deficient mice, and these cells also show impaired migration and tube formation in vitro. Inhibition of MT1-MMP with a neutralizing antibody impairs NOinduced tube formation by human ECs, and NO-induced endothelial migration and tube formation are impaired in lung ECs from mice deficient in MT1-MMP. MT1-MMP thus appears to be a key molecular effector of NO during the EC migration and angiogenic processes, and is a potential therapeutic target for NO-associated vascular disorders.
Description4 Figures. The online version of this article contains a data supplement.
Publisher version (URL)http://bloodjournal.hematologylibrary.org/content/110/8/2916.full
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