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Related Experiment Video

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Lymphatic endothelial mTORC1 instructs metabolic and developmental signaling during lymphangiogenesis.

Fei Han1, Summer Simeroth2, Jie Zhu1

  • 1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

Developmental Cell
|May 8, 2025
PubMed
Summary
This summary is machine-generated.

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates nutrient metabolism and PROX1 expression, crucial for lymphatic development. Loss of mTORC1 impairs lymphatic capillary growth and collecting vessel differentiation.

Keywords:
MycPROX1glutaminaseglutaminolysisglycolysishexokinase 2lymphangiogenesislymphatic endothelial celllymphatic vesselmTORC1

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Area of Science:

  • Vascular Biology
  • Cell Metabolism
  • Developmental Biology

Background:

  • Lymphatic endothelial cells (LECs) require nutrient metabolism for lymphangiogenesis.
  • PROX1 expression is essential for lymphatic specification.
  • Molecular links between LEC nutrient metabolism and PROX1 are unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms linking nutrient metabolism and PROX1 expression in LECs.
  • To investigate the role of mTORC1 in regulating metabolic programs and PROX1 during lymphangiogenesis.

Main Methods:

  • Utilized mouse models with genetic ablation of RAPTOR, a key mTORC1 component.
  • Performed experiments on mouse and human LECs to assess mTORC1 inhibition effects.
  • Analyzed changes in PROX1, Myc, hexokinase 2 (HK2), and glutaminase (GLS) expression.
  • Conducted genetic interaction analyses.

Main Results:

  • Loss of RAPTOR (mTORC1 component) downregulates PROX1 and impairs lymphatic capillary growth and collecting vessel differentiation.
  • mTORC1 inhibition reduces Myc, subsequently decreasing HK2 and GLS, thereby inhibiting glycolysis and glutaminolysis.
  • Ablation of Myc or HK2/GLS hinders lymphatic vessel formation.
  • mTORC1's regulation of PROX1 is independent of Myc-HK2/GLS signaling.
  • Myc and PROX1 are critical for mTORC1-regulated lymphatic development.

Conclusions:

  • mTORC1 is a key regulator of metabolic programs essential for lymphangiogenesis.
  • mTORC1 controls PROX1 expression independently of Myc-mediated metabolic pathways.
  • This study reveals mTORC1 as a central coordinator of LEC metabolism and PROX1 levels during lymphatic development.