Department of Surgery (H.Y., T.Z., B.L.), School of Medicine and Public Health, University of Wisconsin-Madison.
Department of Ophthalmology and Visual Sciences (C.M.S., N.S.), School of Medicine and Public Health, University of Wisconsin-Madison.
Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):e350-e366. doi: 10.1161/ATVBAHA.120.314913. Epub 2020 Oct 8.
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 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 restored the ability of macrophages to invade matrix. Finally, we generated mice and crossed them with mice. In the CaCl-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.
TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.
腹主动脉瘤的特征是主动脉完整性的逐渐丧失和主要是巨噬细胞的炎症细胞的积累。我们之前的研究报告称，基质细胞蛋白 TSP1（血栓素-1）的全局缺失可保护小鼠免于发生动脉瘤。本研究的目的是研究 TSP1 在动脉瘤中的作用的细胞和分子机制。方法和结果：通过 RNA 荧光原位杂交，我们鉴定出巨噬细胞是人类和小鼠动脉瘤组织中 TSP1 的主要来源，占积极表达 mRNA 的细胞的 70%以上。巨噬细胞中 TSP1 的缺乏通过升高 TIMP1（金属蛋白酶组织抑制剂-1）而不影响主要 MMPs（基质金属蛋白酶）来降低基于溶液的明胶酶活性。敲低 恢复了 巨噬细胞侵袭基质的能力。最后，我们生成了 小鼠，并将它们与 小鼠杂交。在氯化钙诱导的腹主动脉瘤模型中，髓样细胞中缺乏 TSP1 足以通过减少巨噬细胞积累和保持主动脉完整性来保护小鼠免于发生动脉瘤。结论：TSP1 通过抑制 TIMP1 的表达促进动脉瘤的发病机制，这随后使炎症性巨噬细胞能够渗透到血管组织中。
