Glycolysis-derived lactate contributes to H3K18la modification and CCL27 expression to promote placental angiogenesis

Numerous studies have shown that impaired placental angiogenesis results in a spectrum of gestational diseases, posing significant risks to both maternal and fetal health. Yet, the metabolic patterns and underlying mechanisms that govern placental angiogenesis remain poorly understood. Here, we examined the metabolic reprogramming during placental development and the role of its metabolic derivative, lactate, in placental angiogenesis and the associated mechanistic pathways. Firstly, a pronounced metabolic shift toward glycolysis, accompanied by significant lactate accumulation, was identified in the early-stage placenta through targeted metabolomics. Then, converging evidence from inhibition of glycolysis, lactate production, and lactate transport demonstrated that disrupted this metabolic axis significantly impaired placental angiogenesis both in vivo and in vitro. However, supplementation with exogenous NaLa rescued this impairment in both model systems. In addition, mechanistically, lactate contributes to H3K18la modification and placental angiogenesis. Subsequently, integrated analysis of CUT&Tag and RNA-seq data identified CCL27 as a potential transcriptional target of H3K18la. Finally, the regulatory role was further supported by gain- and loss-of-function studies, wherein recombinant CCL27 restored angiogenesis while the receptor antagonist BI-6901 suppressed it, suggesting the involvement of the CCL27 in placental angiogenesis. In summary, our work demonstrates that glycolysis-derived lactate is involved in H3K18la modification and may subsequently contribute to CCL27 expression, potentially supporting placental angiogenesis. This work reveals a novel metabolic-epigenetic pathway that coordinately regulates placental vascular development, informing future targeted strategies for pregnancy complications resulted from impaired placental angiogenesis.