Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.
Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.
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DOI：
10.1096/fj.202100484r
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发表时间：
2021-08
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专门的促消退脂质介质Maresin 1（MaR 1）参与组织炎症的消退阶段。据推测，外源性施用MaR 1将通过LGR 6受体信号传导和平滑肌细胞（SMC）的巨噬细胞依赖性巨噬细胞增多以精氨酸依赖性方式减弱腹主动脉瘤（AAA）生长。使用局部弹性蛋白酶AAA模型，在C57 BL/6野生型（WT）小鼠和平滑肌细胞特异性TGF-β2受体敲除（SMC-TGFβr2−/−）小鼠中诱导AAA。与溶剂处理的小鼠相比，MaR 1处理显著减弱了WT小鼠的AAA生长，并增加了主动脉SMC α-肌动蛋白和TGF-β2的表达，但SMC-TGFβr2−/−小鼠没有。在体内，LGR 6受体的抑制消除了AAA形成和SMC α-肌动蛋白表达中的MaR 1依赖性保护作用。此外，MaR 1在AAA形成过程中上调小鼠主动脉组织中凋亡SMCs的巨噬细胞依赖性细胞吞噬作用。体外研究表明，MaR 1-LGR 6相互作用在巨噬细胞凋亡SMC的串扰期间上调TGF-β2表达并降低MMP 2活性。总之，这些结果表明MaRl激活LGR 6受体以上调巨噬细胞依赖性巨噬细胞增多，增加TGF-β表达，保持主动脉壁重塑并减弱AAA形成。因此，本研究证明了MaR 1-LGR 6介导的通过TGF-β2增加凋亡SMC的细胞增殖来减轻血管重塑以减弱AAA形成的潜力。
The specialized pro-resolving lipid mediator Maresin 1 (MaR1) is involved in the resolution phase of tissue inflammation. It was hypothesized that exogenous administration of MaR1 would attenuate abdominal aortic aneurysm (AAA) growth in a cytokine-dependent manner via LGR6 receptor signaling and macrophage-dependent efferocytosis of smooth muscle cells (SMCs). AAAs were induced in C57BL/6 wild-type (WT) mice and smooth muscle cell specific TGF-β2 receptor knockout (SMC-TGFβr2−/−) mice using a topical elastase AAA model. MaR1 treatment significantly attenuated AAA growth as well as increased aortic SMC α-actin and TGF-β2 expressions in WT mice, but not SMC-TGFβr2−/− mice, compared to vehicle-treated mice. In vivo inhibition of LGR6 receptors obliterated MaR1-dependent protection in AAA formation and SMC α-actin expression. Furthermore, MaR1 upregulated macrophage-dependent efferocytosis of apoptotic SMCs in murine aortic tissue during AAA formation. In vitro studies demonstrate that MaR1-LGR6 interaction upregulates TGF-β2 expression and decreases MMP2 activity during crosstalk of macrophage-apoptotic SMCs. In summary, these results demonstrate that MaR1 activates LGR6 receptors to upregulate macrophage-dependent efferocytosis, increases TGF-β expression, preserves aortic wall remodeling and attenuate AAA formation. Therefore, this study demonstrates the potential of MaR1-LGR6 mediated mitigation of vascular remodeling through increased efferocytosis of apoptotic SMCs via TGF-β2 to attenuate AAA formation.