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Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis

S Huber1, C J Bruns, G Schmid

  • 1Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.

Kidney International
|February 15, 2007
PubMed

Insights

Mammalian target of rapamycin (mTOR) inhibitors impede lymphatic vessel repair after injury. This study shows rapamycin inhibits lymphangiogenesis, potentially impacting wound healing and offering therapeutic avenues for cancer.

Area of Science:

  • Immunosuppression and Transplantation
  • Vascular Biology
  • Wound Healing

Background:

  • Lymphatic complications are frequent side effects of mammalian target of rapamycin (mTOR) inhibitor immunosuppression in kidney transplant recipients.
  • The antihemangiogenic effects of mTOR inhibitors are known, but their impact on regenerative lymphangiogenesis remains unclear.

Purpose of the Study:

  • To investigate whether the mTOR inhibitor rapamycin impedes regenerative lymphangiogenesis.
  • To explore the underlying mechanisms of rapamycin's effect on lymphatic endothelial cells (LECs).

Main Methods:

  • A murine skin flap model was used to assess lymphatic flow recovery and wound edema.
  • In vitro studies utilized isolated human LECs to evaluate proliferation and migration inhibition.
  • An in vivo Matrigel lymphangiogenesis assay and a lymphangioma model were employed.

Main Results:

  • Rapamycin impaired lymphatic flow recovery and prolonged wound edema in the murine skin flap model.
  • The antilymphangiogenic effect was specific and not due to general wound healing inhibition.
  • Low concentrations of rapamycin inhibited LEC proliferation and migration, mediated by impaired VEGF signaling.

Conclusions:

  • mTOR inhibition exhibits significant antilymphangiogenic activity, hindering regenerative lymphangiogenesis.
  • Early use of mTOR inhibitors post-tissue injury should be avoided to prevent impaired lymphatic repair.
  • Rapamycin's antilymphangiogenic properties may hold therapeutic potential for treating or preventing malignancies.

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