Supporting data for Inflammatory and metabolic signalling between macrophages, dental pulp stem cells and endothelial cells in the vascular microenvironment.

In the first phase, we demonstrate that M1 macrophages enhance vascular endothelial growth factor (VEGF) secretion by DPSCs, thereby promoting endothelial cell activation and tubulogenesis. This pro-angiogenic signal establishes the foundation for subsequent vascular remodeling. In the second phase, under hypoxic conditions, DPSCs exhibit markedly upregulated VEGF secretion. This DPSC-derived VEGF stimulates lactate production and secretion by endothelial cells through enhanced glycolytic activity. The accumulated extracellular lactate is taken up by neighboring M1 macrophages, where it induces histone lactylation, a novel epigenetic modification. Histone lactylation, particularly at H3K18, triggers transcriptional reprogramming of M1 macrophages, driving their transition toward an M2-like phenotype. These M2-like macrophages secrete factors that promote vascular stabilization, including pericyte recruitment and vessel maturation. Collectively, our findings reveal a multi-cellular signaling cascade wherein DPSCs integrate inflammatory and hypoxic cues to coordinate the transition from active angiogenesis to stabilized vascular networks. This mechanism highlights the therapeutic potential of targeting DPSC-macrophage-endothelial interactions for regenerative dentistry and vascularized tissue engineering applications.