| First Author | Yang H | Year | 2020 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 40 |
| Issue | 12 | Pages | e350-e366 |
| PubMed ID | 33028100 | Mgi Jnum | J:318633 |
| Mgi Id | MGI:6860250 | Doi | 10.1161/ATVBAHA.120.314913 |
| Citation | Yang H, et al. (2020) 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 |
| abstractText | 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 and Results: 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 Thbs1 (flox/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. |
