Vascular endothelial growth factor (VEGF) is one of the most powerful proangiogenic factors and plays an important role in multiple diseases. Increased glycolytic rates and lactate accumulation are associated with pathological angiogenesis. Here, we show that a feedback loop between H3K9 lactylation (H3K9la) and histone deacetylase 2 (HDAC2) in endothelial cells drives VEGF-induced angiogenesis. We find that the H3K9la levels are upregulated in endothelial cells in response to VEGF stimulation. Pharmacological inhibition of glycolysis decreases H3K9 lactylation and attenuates neovascularization. CUT& Tag analysis reveals that H3K9la is enriched at the promoters of a set of angiogenic genes and promotes their transcription. Interestingly, we find that hyperlactylation of H3K9 inhibits expression of the lactylation eraser HDAC2, whereas overexpression of HDAC2 decreases H3K9 lactylation and suppresses angiogenesis. Collectively, our study illustrates that H3K9la is important for VEGF-induced angiogenesis, and interruption of the H3K9la/HDAC2 feedback loop may represent a novel therapeutic method for treating pathological neovascularization.

中文翻译：

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内皮细胞中由 H3K9 乳酰化和 HDAC2 驱动的反馈环路调节 VEGF 诱导的血管生成


血管内皮生长因子（VEGF）是最强大的促血管生成因子之一，在多种疾病中发挥着重要作用。糖酵解速率和乳酸积累增加与病理性血管生成有关。在这里，我们发现内皮细胞中 H3K9 乳酰化 (H3K9la) 和组蛋白脱乙酰酶 2 (HDAC2) 之间的反馈回路驱动 VEGF 诱导的血管生成。我们发现内皮细胞中 H3K9la 水平响应 VEGF 刺激而上调。糖酵解的药理抑制可降低 H3K9 乳酰化并减弱新血管形成。 CUT&Tag 分析表明，H3K9la 在一组血管生成基因的启动子处富集并促进其转录。有趣的是，我们发现H3K9的过度乳酰化会抑制乳酰化擦除器HDAC2的表达，而HDAC2的过度表达会降低H3K9的乳酰化并抑制血管生成。总的来说，我们的研究表明 H3K9la 对于 VEGF 诱导的血管生成很重要，并且 H3K9la/HDAC2 反馈环路的中断可能代表一种治疗病理性新生血管形成的新治疗方法。