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Kidney Int ; 71(8): 771-7, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17299523

RESUMO

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 Matrigeltrade mark 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.


Assuntos
Células Endoteliais/efeitos dos fármacos , Endotélio Linfático/efeitos dos fármacos , Imunossupressores/farmacologia , Linfangiogênese/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno , Combinação de Medicamentos , Imunossupressores/uso terapêutico , Laminina , Linfangioma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Peritoneais/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Proteoglicanas , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator C de Crescimento do Endotélio Vascular/efeitos dos fármacos
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