Myeloid-Derived TSP1 (Thrombospondin-1) Contributes to Abdominal Aortic Aneurysm Through Suppressing Tissue Inhibitor of Metalloproteinases-1.
Arterioscler Thromb Vasc Biol
; 40(12): e350-e366, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-33028100
ABSTRACT
OBJECTIVE:
Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1's action in aneurysm. Approach andResults:
Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1-/- macrophages to invade matrix. Finally, we generated Thbs1flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl2-induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity.CONCLUSIONS:
TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Aorta Abdominal
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Aneurisma da Aorta Abdominal
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Inibidor Tecidual de Metaloproteinase-1
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Trombospondina 1
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Macrófagos
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article