Open AccessEndothelial MT 1‐ MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis
Author(s) -
Esteban Sergio,
Clemente Cristina,
Koziol Agnieszka,
Gonzalo Pilar,
Rius Cristina,
Martínez Fernando,
Linares Pablo M,
Chaparro María,
Urzainqui Ana,
Andrés Vicente,
Seiki Motoharu,
Gisbert Javier P,
Arroyo Alicia G
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910862
Subject(s) - angiogenesis , intravital microscopy , thrombospondin 1 , in vivo , colitis , nitric oxide , cancer research , matrix metalloproteinase , endothelial stem cell , chemistry , immunology , medicine , pathology , biology , in vitro , biochemistry , microbiology and biotechnology
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 MT 1‐ MMP in endothelial cells ( MT 1 iΔ 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 MT 1‐ 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 MT 1‐ MMP substrate thrombospondin‐1 ( TSP 1) to CD 47/αvβ3 integrin. Moreover, TSP 1 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 TSP 1 reduced IA during mouse colitis. Our results identify MT 1‐ MMP as a new actor in inflammatory IA and a promising therapeutic target for inflammatory bowel disease.