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<p>Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, is associated with enhanced thrombosis. However, its impact on endothelial function and angiogenesis remains unclear. A murine hindlimb ischemia model was used to assess perfusion recovery. Human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation were evaluated in vitro. Gene set enrichment analysis (GSEA) was performed for pathway enrichment analyses. Furthermore, glycolytic flux and enzyme expression were measured. Lentiviral lactate dehydrogenase A (LDHA) overexpression was performed both in vitro and in vivo. Elevated PAGln impaired blood flow recovery and inhibited HUVEC proliferation, migration and tube formation. β-receptor blocker zenidolol was able to reverse the adverse effects. PAGln downregulated glycolytic pathways, reduced proton efflux, and suppressed LDHA expression and lactate production. LDHA overexpression rescued PAGln-induced angiogenic impairment. The gut metabolite PAGln may suppress angiogenesis of HUVEC by targeting the β-receptors, subseqeuently inhibiting LDHA expression.</p> Graphical Abstract <p></p>

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The Gut Metabolite Phenylacetylglutamine Inhibits the Angiogenic Potential of Human Umbilical Vein Endothelial Cells Via the β-Adrenergic Receptor-LDHA Axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月24日

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  • Yin Zhang,
  • Wenlong Yang,
  • Jinyan Zhang,
  • Jixiang A,
  • Jinye Shen,
  • Zhiyong Qi,
  • Juying Qian,
  • Aijun Sun,
  • Junbo Ge,
  • Shuning Zhang

摘要

Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, is associated with enhanced thrombosis. However, its impact on endothelial function and angiogenesis remains unclear. A murine hindlimb ischemia model was used to assess perfusion recovery. Human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation were evaluated in vitro. Gene set enrichment analysis (GSEA) was performed for pathway enrichment analyses. Furthermore, glycolytic flux and enzyme expression were measured. Lentiviral lactate dehydrogenase A (LDHA) overexpression was performed both in vitro and in vivo. Elevated PAGln impaired blood flow recovery and inhibited HUVEC proliferation, migration and tube formation. β-receptor blocker zenidolol was able to reverse the adverse effects. PAGln downregulated glycolytic pathways, reduced proton efflux, and suppressed LDHA expression and lactate production. LDHA overexpression rescued PAGln-induced angiogenic impairment. The gut metabolite PAGln may suppress angiogenesis of HUVEC by targeting the β-receptors, subseqeuently inhibiting LDHA expression.

Graphical Abstract