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DLL4 and Jagged1 are angiogenic targets of orphan nuclear receptor TR3/Nur77

Jin Peng1, Shengqiang Zhao2, Yan Li2

  • 1Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Radiotherapy and Medical Oncology Department, Zhongnan Hospital, Wuhan University, Wuhan, PR China.

Microvascular Research
|April 2, 2019
PubMed

Insights

Orphan nuclear receptor TR3/Nur77 regulates angiogenesis by controlling DLL4 and Jagged1 expression, impacting sepsis outcomes. TR3/Nur77 is a promising therapeutic target for sepsis and related diseases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Pathological angiogenesis is implicated in numerous diseases.
  • Orphan nuclear receptor TR3/Nur77 was previously identified as a key regulator of angiogenesis, influencing tumor growth and wound healing.
  • The precise molecular mechanisms underlying TR3/Nur77's role in angiogenesis require further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TR3/Nur77 regulates angiogenesis.
  • To identify specific molecular fragments of TR3/Nur77 involved in this regulation.
  • To explore the therapeutic potential of targeting TR3/Nur77 in disease models, particularly sepsis.

Main Methods:

  • Utilized cultured endothelial cells to examine the effect of TR3/Nur77 fragments on DLL4 and Jagged 1 expression.
  • Investigated the interplay between TR3/Nur77, integrins, DLL4, and Jagged 1 in angiogenic responses.
  • Analyzed TR3/Nur77, DLL4, Jagged 1, and integrin expression in animal models of sepsis (LPS-induced endotoxemia and cecal ligation and puncture).
  • Assessed survival rates in TR3/Nur77 knockout mice subjected to sepsis models.

Main Results:

  • TR3/Nur77 fragments were found to regulate DLL4 and Jagged 1 expression in endothelial cells.
  • DLL4 and Jagged 1 mediated TR3/Nur77-induced angiogenic responses, while integrins regulated DLL4 and Jagged 1 expression induced by TR3/Nur77.
  • TR3/Nur77, DLL4, Jagged 1, and specific integrins (α1, α2, β3, β5) were modulated in sepsis models.
  • TR3/Nur77 expression was transiently increased during sepsis.
  • Nur77 knockout mice exhibited significantly improved survival rates in both sepsis models.
  • A novel signaling axis (VEGF/histamine ➔ TR3/Nur77 ➔ integrins ➔ DLL4/Jagged1) in angiogenesis was elucidated.

Conclusions:

  • TR3/Nur77 plays a critical role in regulating angiogenesis through the novel axis involving integrins, DLL4, and Jagged 1.
  • TR3/Nur77 emerges as a significant therapeutic target for sepsis, with targeting offering improved survival outcomes.
  • These findings deepen the understanding of TR3/Nur77's molecular mechanisms in angiogenesis and its therapeutic potential.
Keywords:
AngiogenesisDLL4IntegrinJagged1SepsisTR3/Nur77

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