Research Paper Volume 11, Issue 19 pp 8604—8622

Tryptophan metabolite 5-methoxytryptophan ameliorates arterial denudation-induced intimal hyperplasia via opposing effects on vascular endothelial and smooth muscle cells

Figure 9. Schematic illustration of vascular protective actions of 5-MTP. In response to arterial denudation injury, inflammatory mediators IL-1β and TNF-α are released in the injured site. TNF-α inhibits VEGFR2 activation in endothelial cells (ECs). 5-MTP mitigates TNF-α-inhibited VEGFR2 phosphorylation, leading to EC proliferation and migration and consequent reendothelialization to protect blood vessels. In VSMCs, the inflammatory mediators activate NFκB and p38 MAPK pathways that lead to downregulation of transcription factor SRF and its cofactor MRTF-A, resulting in reduced expression of VSMC markers and converting to a synthetic phenotype of VSMCs. 5-MTP suppresses phosphorylation of NFκB and p38 MAPK, preventing downregulation of SRF and MRTF-A and sustaining expressions of VSMC markers. As such, 5-MTP inhibits VSMC proliferation and migration, and maintains differentiated phenotype of VSMCs. Ultimately, through combinatorial but opposing effects on ECs and VSMCs, 5-MTP protects against arterial injury-induced intimal hyperplasia.