Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation
Craig T. Elder, Amanda C. Filiberto, Gang Su, Zachary Ladd, Victoria Leroy, Eric Y. Pruitt, Guanyi Lu, Zhihua Jiang, Ashish K. Sharma, Gilbert R. Upchurch
Abstract
Abstract 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.