Genís, LauraGonzalo, PilarTutor, Antonio SGálvez, Beatriz GMartínez-Ruiz, AntonioZaragoza, CarlosLamas, SantiagoTryggvason, KarlApte, Suneel SArroyo, Alicia G2026-03-252026-03-252007-10-15Blood. 2007 Oct 15;110(8):2916-23.https://hdl.handle.net/20.500.12105/27351Nitric 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.We thank S. Bartlett for editing and D. Megı´as and Dr M. Montoya for assistance with confocal microscopy. This work was supported by National Institutes of Health grant AR47074 (S.A.), Comunidad Auto´noma de Madrid grants CAM 08.4/0023/2003 (C.Z.) and GR/SAL/0309/2004 (A.G.A.), Spanish Ministerio de Sanidad y Consumo grant CP03/00 025 (A.M.R.), and Spanish Ministerio de Educación y Ciencia grants SAF2005-06025 (C.Z.), SAF2006-02410 (S.L.), and SAF2005-02228 (A.G.A.). P.G. is a postdoctoral researcher from the “Juan de la Cierva” program (MCyT) and C.Z. is a research investigator from the “Ramón y Cajal” program (MCyT).enghttp://creativecommons.org/licenses/by-nc-nd/4.0/research articleAttribution-NonCommercial-NoDerivatives 4.0 International17606763Bloodopen access