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- Title
Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis.
- Authors
Huber, S.; Bruns, C. J.; Schmid, G.; Hermann, P. C.; Conrad, C.; Niess, H.; Huss, R.; Graeb, C.; Jauch, K.-W.; Heeschen, C.; Guba, M.
- Abstract
Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigel™ lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.Kidney International (2007) 71, 771–777. doi:10.1038/sj.ki.5002112; published online 14 February 2007
- Subjects
EDEMA; VASCULAR endothelial growth factors; COMPLICATIONS from organ transplantation; RAPAMYCIN; KIDNEY transplantation
- Publication
Kidney International, 2007, Vol 71, Issue 8, p771
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/sj.ki.5002112