Objectives: In response to injury, vascular smooth muscle cells (VSMCs) undergo a phenotypic transition whereby they proliferate and migrate from the medial layer into the intima, contributing to neointima formation. 5-Methoxytryptophan (5-MTP) is a 5-methoxyindole metabolite of tryptophan metabolism, was recently shown to suppress inflammatory mediator-induced cancer cell proliferation and migration. However, the role of 5-MTP in vascular cells is unclear. The aim of this study was to investigate whether 5-MTP plays a role in modulating VSMC phenotypes and vascular remodeling following arterial injury. Methods: C57BL/6 mice were subjected to femoral artery endoluminal injury, treated with vehicle or 5-MTP, and arteries harvested 4 weeks later for histological analysis. Proinflammatory cytokine interleukin-1β (IL-1β) is increased in the injured vessel wall, thus we examined whether IL-1β affected VSMC phenotypic modulation. Primary cultured VSMCs were treated with or without IL-1β in the presence or absence of 5-MTP. The effects of 5-MTP on IL-1β-mediated VSMC proliferation, marker gene expressions, and signaling pathways were examined. Results: H&E and Verhoeff’s elastin staining revealed that compared with vehicle-treated mice, 5-MTP significantly decreased intimal thickening after arterial injury. Immunostaining of arterial sections showed that 5-MTP attenuated injury-mediated matrix metalloproteinase-2 (MMP2) upregulation and smooth muscle (SM) α-actin downregulation. Western blot analysis revealed that 5-MTP prevented IL-1β-mediated alterations of SM α-actin and MMP2. Furthermore, 5-MTP decreased IL-1β-induced cell proliferation and p38 MAPK activation. Conclusions: Our data indicate a protective role of 5-MTP against arterial injury-induced neointimal formation. Mechanistically, 5-MTP might exert its vascular effects via modulating VSMC phenotypes through p38 MAPK pathway.
