Endothelial MT1‐MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis
| Autor: | María Chaparro, Pilar Gonzalo, Agnieszka Koziol, Fernando Martínez, Ana Urzainqui, Javier P. Gisbert, Vicente Andrés, Alicia G. Arroyo, Pablo M. Linares, Cristina Clemente, Sergio Esteban, Motoharu Seiki, Cristina Rius |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Fundación ProCNIC, Ministerio de Economía y Competitividad (España), Clemente, Cristina [0000-0002-5831-9132], Gonzalo, Pilar [0000-0001-8811-8369], Martínez, Fernando [0000-0003-0908-9366], Linares, Pablo M. [0000-0003-4090-6942], Chaparro, María [0000-0002-9275-4242], Urzainqui, Ana [0000-0001-9326-6112], Andrés, Vicente [0000-0002-0125-7209], Seiki, Motoharu [0000-0002-3909-0782], Gisbert, Javier P. [0000-0003-2090-3445], Arroyo, Alicia G. [0000-0002-1536-3846], Clemente, Cristina, Gonzalo, Pilar, Martínez, Fernando, Linares, Pablo M., Chaparro, María, Urzainqui, Ana, Andrés, Vicente, Seiki, Motoharu, Gisbert, Javier P., Arroyo, Alicia G. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Medicine (General) Vascular Biology & Angiogenesis Matrix Metalloproteinases Membrane-Associated QH426-470 Matrix metalloproteinase Inflammatory bowel disease Article MT1‐MMP Nitric oxide TSP1 03 medical and health sciences chemistry.chemical_compound R5-920 0302 clinical medicine In vivo inflammatory bowel disease nitric oxide MT1-MMP Genetics medicine Matrix Metalloproteinase 14 Intussusceptive angiogenesis Humans Colitis intussusceptive angiogenesis Neovascularization Pathologic CD47 Endothelial Cells Metalloendopeptidases Articles medicine.disease 030104 developmental biology chemistry Cancer research Molecular Medicine Genetics Gene Therapy & Genetic Disease Digestive System 030217 neurology & neurosurgery Intravital microscopy |
| Zdroj: | EMBO Molecular Medicine Repisalud Instituto de Salud Carlos III (ISCIII) Digital.CSIC. Repositorio Institucional del CSIC instname EMBO Molecular Medicine, Vol 12, Iss 2, Pp n/a-n/a (2020) |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | 22 p.-9 fig. 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 (MT1(i Delta EC)) 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/alpha v beta 3 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 alpha v beta 3 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. This study was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (SAF2014-52050-R and SAF2017-83229-R to A.G.A). S. |
| Databáze: | OpenAIRE |
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