Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis.
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.
Huber
S
S
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Bruns
C J
CJ
Schmid
G
G
Hermann
P C
PC
Conrad
C
C
Niess
H
H
Huss
R
R
Graeb
C
C
Jauch
K-W
KW
Heeschen
C
C
Guba
M
M
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects*; D004729:Endothelium, Lymphatic / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007797:Laminin; D042583:Lymphangiogenesis / Q000187:drug effects*; D008202:Lymphangioma / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects*; D011509:Proteoglycans; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000187:drug effects
D004338:Drug Combinations; D007166:Immunosuppressive Agents; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C059485:matrigel; D003094:Collagen; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus