Background <p>Aberrant angiogenesis is an important pathological feature of periodontitis, which is regulated by angiogenic paracrine factors derived from periodontal ligament stem cells (PDLSCs). We have previously demonstrated that ubiquitin C-terminal hydrolase L1 (UCHL1) was upregulated in PDLSCs from periodontitis patients, but its role in aberrant angiogenesis in periodontitis remains unclear.</p> Methods <p>PDLSCs were isolated from healthy individuals and periodontitis patients. To mimic inflammatory conditions in vitro, PDLSCs from healthy individuals were treated with tumor necrosis factor-alpha and interleukin-1beta. Human umbilical vein endothelial cells were cultured with conditioned media from PDLSCs, and their proliferation, migration, and tube formation were detected to evaluate the pro-angiogenic capacity of PDLSCs. Vascular endothelial growth factor A (VEGFA) and angiopoietin 1 (ANGPT1) levels were measured using RT-qPCR, Western blotting, Immunofluorescence, and enzyme-linked immunosorbent assay. UCHL1 was knocked down using shRNA to validate its function and regulation of Yes-associated protein (YAP) activity. Co-immunoprecipitation was used to verify the interaction of UCHL1 with hypoxia-inducible factor 1 alpha (HIF-1α), and chromatin immunoprecipitation was used to analyze the effect of HIF-1α on YAP transcription. UCHL1 inhibitor was administered in a periodontitis murine model to investigate its function in vivo.</p> Results <p>The pro-angiogenic capacity of PDLSCs from periodontitis patients was enhanced, accompanied by increased expressions of VEGFA and ANGPT1, which were positively correlated with UCHL1 expression. UCHL1 knockdown in PDLSCs abrogated the increased secretion of VEGFA and ANGPT1 and the enhanced pro-angiogenic capacity under inflammatory conditions. Mechanistically, UCHL1 functioned through facilitating YAP expression and nuclear translocation, a process that was mediated by the stabilization and activation of HIF-1α, which in turn promoted YAP transcription. In vivo inhibition of UCHL1 in a periodontitis murine model alleviated aberrant angiogenesis and reduced the expressions of VEGFA and ANGPT1, thus attenuating periodontitis progression by reducing lymphocyte infiltration, inflammatory cytokine levels, and alveolar bone resorption.</p> Conclusions <p>This study demonstrated that UCHL1 promoted the pro-angiogenic capacity of PDLSCs in periodontitis through the HIF-1α/YAP signaling, which provides insights into the&#xa0;pathogenesis of periodontitis and paves the way for novel treatment strategies.</p>