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Introduction <p>Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF.</p> Materials and methods <p>Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays.</p> Results <p>Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA.</p> Conclusions <p>VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.</p>

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Bradykinin reduces wound healing in human umbilical vein endothelial cells via downregulation of vascular endothelial growth factor A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月10日

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  • Nevena Dimitrova,
  • Angelina Gierke,
  • Raphael Möhrle,
  • Julia Nemeth,
  • Cornelia Brunner,
  • Thomas K. Hoffmann,
  • Jens Greve,
  • Janina Hahn,
  • Robin Lochbaum

摘要

Introduction

Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF.

Materials and methods

Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays.

Results

Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA.

Conclusions

VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.