Tenascin C+ myofibroblasts exacerbate vascular neointimal hyperplasia by propagation of nerve-macrophage interactions in mice

Neointimal hyperplasia (NIH) is a major pathological feature of vascular injury, yet its cellular and molecular drivers remain elusive. Here, using a mouse model of ligation-induced carotid artery NIH, we identify a population of Tenascin C-expressing (Tnc⁺) myofibroblasts (MF). We demonstrate a TNC-driven transition of adventitial fibroblasts (AF) into Tnc⁺ MFs via integrin αvβ1, initiating a positive feedback loop that sustains MF accumulation. In vitro, Tnc⁺ MFs enhance neurite outgrowth, and in vivo, they spatially associate with aberrant axon growth and macrophage accumulation in the perivascular niche. Mechanistically, TNC-activated sensory nerves release CCL2 to recruit macrophages and position them along growing axons. Fibroblast-specific Tnc deletion or sensory neuron inhibition attenuates perivascular hyperinnervation, macrophage recruitment, and neointimal thickening. Importantly, we observe aberrant nerve fibers and macrophage infiltration in human NIH specimens. Thus, we describe a TNC-driven fibroblast-nerve-macrophage axis that sustains inflammation and promotes vascular remodeling. Targeting TNC may offer new therapeutic avenues for vascular diseases. The interaction between immune cells and the peripheral nervous system during the progression of vascular diseases is poorly understood. Here, the authors use a mouse model of neointimal hyperplasia (NIH) and show that Tenascin (Tnc)-positive myofibroblasts originate from adventitial fibroblasts and promote activation of sensory nerves and CCL-2-dependent accumulation of macrophages to drive inflammation and vascular remodeling.