%0 Journal Article
%A Genís, Laura
%A Gonzalo, Pilar
%A Tutor, Antonio S.
%A Gálvez, Beatriz G.
%A Martínez Ruiz, Antonio
%A Zaragoza, Carlos
%A Lamas, Santiago
%A Tryggvason, Karl
%A Apte, Suneel S.
%A Arroyo, Alicia G.
%T Functional interplay between endothelial nitric oxide synthase and membrane type 1–matrix metalloproteinase in migrating endothelial cells
%D 2007
%@ 0006-4971
%@ 1528-0020
%U https://hdl.handle.net/20.500.14352/102744
%X Nitric 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 motilityassociated 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 NOinduced 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 migrationand angiogenic processes, and is a potential therapeutic target for NO-associated vascular disorders.
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