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oai:repisalud.isciii.es:20.500.12105/96312024-09-27T09:05:21Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605col_20.500.12105_19607

00925njm 22002777a 4500 dc Esteban, Sergio author Clemente, Cristina author Koziol, Agnieszka author Gonzalo, Pilar author Rius, Cristina author Martinez, Fernando author Linares, Pablo M author Chaparro, María author Urzainqui, Ana author Andres, Vicente author Seiki, Motoharu author Gisbert, Javier P author Arroyo, Alicia G author 2020-02 Pathological angiogenesis contributes to cancer progression and chronic inflammatory diseases. In inflammatory bowel disease, the microvasculature expands by intussusceptive angiogenesis (IA), a poorly characterized mechanism involving increased blood flow and splitting of pre-existing capillaries. In this report, mice lacking the protease MT1-MMP in endothelial cells (MT1iΔEC ) presented limited IA in the capillary plexus of the colon mucosa assessed by 3D imaging during 1% DSS-induced colitis. This resulted in better tissue perfusion, preserved intestinal morphology, and milder disease activity index. Combined in vivo intravital microscopy and lentiviral rescue experiments with in vitro cell culture demonstrated that MT1-MMP activity in endothelial cells is required for vasodilation and IA, as well as for nitric oxide production via binding of the C-terminal fragment of MT1-MMP substrate thrombospondin-1 (TSP1) to CD47/αvβ3 integrin. Moreover, TSP1 levels were significantly higher in serum from IBD patients and in vivo administration of an anti-MT1-MMP inhibitory antibody or a nonamer peptide spanning the αvβ3 integrin binding site in TSP1 reduced IA during mouse colitis. Our results identify MT1-MMP as a new actor in inflammatory IA and a promising therapeutic target for inflammatory bowel disease. EMBO Mol Med. 2020; 12(2):e10862 10.15252/emmm.201910862 1757-4684 1757-4676 EMBO molecular medicine 31793743 http://hdl.handle.net/20.500.12105/9631 MT1-MMP TSP1 Inflammatory bowel disease Intussusceptive angiogenesis Nitric oxide Endothelial MT1-MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis