Perivascular mesenchymal cells instruct ST2+ reparative macrophages to promote endovascular injury-induced neointimal hyperplasia in mice.

Tissue-resident mesenchymal stromal cells (MSC) instruct immune cell activation at injury sites, a key event in tissue repair. However, the full array of immunomodulatory mechanisms driving injury-responsive immune-stromal cell interactions is underexplored. Here, using an endovascular injury mouse model, we demonstrate that perivascular MSCs enhance arterial immune response by facilitating recruitment of ST2-expressing reparative macrophages in male mice. Time-resolved single-cell sequencing reveals an MSC-mediated, macrophage phenotypic switch, essential for vascular regeneration. Mechanistically, injury activates NFκB-dependent IL-33 production in MSCs, which acts as a paracrine signal that drives Osteopontin (OPN/SPP1) production in ST2+ macrophages and stimulates vascular smooth muscle cell (VSMC) proliferation and neointima formation. Local hydrogel-mediated delivery of siRNAs targeting Il33 or Spp1 effectively alleviates injury-induced neointimal hyperplasia, suggesting a potential therapeutic strategy to prevent restenosis and other vascular diseases. Our findings define an IL33-ST2-OPN axis that mediates functional crosstalk between perivascular MSCs and reparative macrophages, orchestrating immune-mediated reparative responses.