Gingival fibroblasts protect against experimental abdominal aortic aneurysm development and rupture through tissue inhibitor of metalloproteinase-1 production

TY - JOUR

T1 - Gingival fibroblasts protect against experimental abdominal aortic aneurysm development and rupture through tissue inhibitor of metalloproteinase-1 production

AU - Giraud, Andreas

AU - Zeboudj, Lynda

AU - Vandestienne, Marie

AU - Joffre, Jérémie

AU - Esposito, Bruno

AU - Potteaux, Stéphane

AU - Vilar, José

AU - Cabuzu, Daniela

AU - Kluwe, Johannes

AU - Seguier, Sylvie

AU - Tedgui, Alain

AU - Mallat, Ziad

AU - Lafont, Antoine

AU - Ait-Oufella, Hafid

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Aims: Abdominal aortic aneurysm (AAA), frequently diagnosed in old patients, is characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix destruction. Despite improvement in the understanding of the pathophysiology of aortic aneurysm, no pharmacological treatment is yet available to limit dilatation and/or rupture. We previously reported that human gingival fibroblasts (GFs) can reduce carotid artery dilatation in a rabbit model of elastase-induced aneurysm. Here, we sought to investigate the mechanisms of GF-mediated vascular protection in two different models of aortic aneurysm growth and rupture in mice.Methods and results: In vitro, mouse GFs proliferated and produced large amounts of anti-inflammatory cytokines and tissue inhibitor of metalloproteinase-1 (Timp-1). GFs deposited on the adventitia of abdominal aorta survived, proliferated, and organized as a layer structure. Furthermore, GFs locally produced Il-10, TGF-β, and Timp-1. In a mouse elastase-induced AAA model, GFs prevented both macrophage and lymphocyte accumulations, matrix degradation, and aneurysm growth. In an Angiotensin II/anti-TGF-β model of aneurysm rupture, GF cell-based treatment limited the extent of aortic dissection, prevented abdominal aortic rupture, and increased survival. Specific deletion of Timp-1 in GFs abolished the beneficial effect of cell therapy in both AAA mouse models.Conclusions: GF cell-based therapy is a promising approach to inhibit aneurysm progression and rupture through local production of Timp-1.

AB - Aims: Abdominal aortic aneurysm (AAA), frequently diagnosed in old patients, is characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix destruction. Despite improvement in the understanding of the pathophysiology of aortic aneurysm, no pharmacological treatment is yet available to limit dilatation and/or rupture. We previously reported that human gingival fibroblasts (GFs) can reduce carotid artery dilatation in a rabbit model of elastase-induced aneurysm. Here, we sought to investigate the mechanisms of GF-mediated vascular protection in two different models of aortic aneurysm growth and rupture in mice.Methods and results: In vitro, mouse GFs proliferated and produced large amounts of anti-inflammatory cytokines and tissue inhibitor of metalloproteinase-1 (Timp-1). GFs deposited on the adventitia of abdominal aorta survived, proliferated, and organized as a layer structure. Furthermore, GFs locally produced Il-10, TGF-β, and Timp-1. In a mouse elastase-induced AAA model, GFs prevented both macrophage and lymphocyte accumulations, matrix degradation, and aneurysm growth. In an Angiotensin II/anti-TGF-β model of aneurysm rupture, GF cell-based treatment limited the extent of aortic dissection, prevented abdominal aortic rupture, and increased survival. Specific deletion of Timp-1 in GFs abolished the beneficial effect of cell therapy in both AAA mouse models.Conclusions: GF cell-based therapy is a promising approach to inhibit aneurysm progression and rupture through local production of Timp-1.

KW - Angiotensin II

KW - Animals

KW - Aorta, Abdominal

KW - Aortic Aneurysm, Abdominal

KW - Aortic Rupture

KW - Disease Models, Animal

KW - Extracellular Matrix

KW - Fibroblasts

KW - Gingiva

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Protective Agents

KW - Tissue Inhibitor of Metalloproteinase-1

KW - Transforming Growth Factor beta

KW - Journal Article

U2 - 10.1093/cvr/cvx110

DO - 10.1093/cvr/cvx110

M3 - SCORING: Journal article

C2 - 28582477

VL - 113

SP - 1364

EP - 1375

JO - CARDIOVASC RES

JF - CARDIOVASC RES

SN - 0008-6363

IS - 11

ER -