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<p>Epigenetic therapy has gained interest in treating cardiovascular diseases, but preclinical studies often encounter challenges with cell-type-specific effects or batch-to-batch variation, which have limited identification of novel drug candidates targeting angiogenesis. To address these limitations and improve the reproducibility of epigenetic drug screening, we redesigned a 3D in vitro fibrin bead assay to utilize immortalized human aortic endothelial cells (TeloHAECs) and screened a focused compound library with 105 agents. Compared to the established model using primary human umbilical vein endothelial cells, TeloHAECs needed a higher-density fibrin gel for optimal sprouting, successfully forming sprouts under both normoxic and hypoxic cell culture conditions. We identified two epigenetic enzyme inhibitors as novel regulators of sprouting angiogenesis: A196, a selective SUV4-20H1/H2 inhibitor, demonstrated pro-angiogenic effects through increased H4K20me1 levels and upregulation of cell cycle associated genes, including <i>MCM2</i> and <i>CDK4.</i> In contrast TMP-269, a selective class IIa HDAC inhibitor, exhibited anti-angiogenic effects by downregulating angiogenesis-related proteins and upregulating pro-inflammatory signaling. These findings highlight the suitability of the modified TeloHAEC fibrin bead assay for drug screening purposes and reveal both pro-angiogenic and anti-angiogenic drug candidates with therapeutic potential.</p>

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Epigenetic drug screening identifies enzyme inhibitors A-196 and TMP-269 as novel regulators of sprouting angiogenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月10日

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  • M. Beter,
  • H. H. Pulkkinen,
  • T. Örd,
  • A. Sormunen,
  • L. Kilpeläinen,
  • J. E. Dunford,
  • M. U. Kaikkonen,
  • E. Aavik,
  • N. Laham-Karam,
  • U. Oppermann,
  • J. P. Laakkonen,
  • S. Ylä-Herttuala

摘要

Epigenetic therapy has gained interest in treating cardiovascular diseases, but preclinical studies often encounter challenges with cell-type-specific effects or batch-to-batch variation, which have limited identification of novel drug candidates targeting angiogenesis. To address these limitations and improve the reproducibility of epigenetic drug screening, we redesigned a 3D in vitro fibrin bead assay to utilize immortalized human aortic endothelial cells (TeloHAECs) and screened a focused compound library with 105 agents. Compared to the established model using primary human umbilical vein endothelial cells, TeloHAECs needed a higher-density fibrin gel for optimal sprouting, successfully forming sprouts under both normoxic and hypoxic cell culture conditions. We identified two epigenetic enzyme inhibitors as novel regulators of sprouting angiogenesis: A196, a selective SUV4-20H1/H2 inhibitor, demonstrated pro-angiogenic effects through increased H4K20me1 levels and upregulation of cell cycle associated genes, including MCM2 and CDK4. In contrast TMP-269, a selective class IIa HDAC inhibitor, exhibited anti-angiogenic effects by downregulating angiogenesis-related proteins and upregulating pro-inflammatory signaling. These findings highlight the suitability of the modified TeloHAEC fibrin bead assay for drug screening purposes and reveal both pro-angiogenic and anti-angiogenic drug candidates with therapeutic potential.