Nrf2 regulates monocyte/macrophage recruitment during initial stages of neointimal formation after vascular injury

Monocyte/macrophage recruitment and adhesion to the intimal region sites after vascular injury initiate arteriosclerosis and subsequent vascular occlusive diseases. The Nrf2 system, a key transcriptional regulator of the oxidative stress response, has been implicated in various stages of vascular remodeling in response to injury and arteriosclerosis. However, its functional significance in monocyte/macrophage recruitment and adhesion in the initial stages of neointimal expansion remains poorly understood. This study found that within 7 days after mechanical arterial injury in mice, Nrf2 was highly expressed in macrophages (F4/80⁺) located on the intimal region sites. Monocyte chemoattractant protein-1 (MCP-1), a potent mediator of monocyte/macrophage attraction, promotes Nrf2 nuclear translocation and induces target genes, including heme oxygenase-1 and thioredoxin-1. Nrf2 deficiency enhances MCP-1-stimulated macrophage chemotaxis and reactive oxygen species production. In vivo, macrophage recruitment and adhesion to the intimal region sites after vascular injury were enhanced in Nrf2-deficient (Nrf2^-/-) mice. By transplanting wild-type (WT)-bone marrow cells into Nrf2^-/- mice, macrophage recruitment and adhesion decreased, but when transplanting Nrf2^-/- bone marrow cells into WT mice, reverse effects occurred. Therefore, the Nrf2 system may regulate MCP-1-stimulated monocyte/macrophage recruitment and adhesion in the initial stages of vascular remodeling after neointimal injury.