PMID- 17299523
OWN - NLM
STAT- MEDLINE
DCOM- 20070618
LR  - 20220419
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 71
IP  - 8
DP  - 2007 Apr
TI  - Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis.
PG  - 771-7
AB  - 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.
FAU - Huber, S
AU  - Huber S
AD  - Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, 
      Munich, Germany.
FAU - Bruns, C J
AU  - Bruns CJ
FAU - Schmid, G
AU  - Schmid G
FAU - Hermann, P C
AU  - Hermann PC
FAU - Conrad, C
AU  - Conrad C
FAU - Niess, H
AU  - Niess H
FAU - Huss, R
AU  - Huss R
FAU - Graeb, C
AU  - Graeb C
FAU - Jauch, K-W
AU  - Jauch KW
FAU - Heeschen, C
AU  - Heeschen C
FAU - Guba, M
AU  - Guba M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070214
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Drug Combinations)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Laminin)
RN  - 0 (Proteoglycans)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factor C)
RN  - 119978-18-6 (matrigel)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Kidney Int. 2007 Apr;71(8):717-9. PMID: 17429417
MH  - Animals
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Collagen
MH  - Drug Combinations
MH  - Endothelial Cells/*drug effects
MH  - Endothelium, Lymphatic/*drug effects
MH  - Immunosuppressive Agents/*pharmacology/therapeutic use
MH  - Laminin
MH  - Lymphangiogenesis/*drug effects
MH  - Lymphangioma/drug therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Peritoneal Neoplasms/drug therapy
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*drug effects
MH  - Proteoglycans
MH  - Ribosomal Protein S6 Kinases, 70-kDa/drug effects
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/drug effects
MH  - Vascular Endothelial Growth Factor C/drug effects
EDAT- 2007/02/15 09:00
MHDA- 2007/06/19 09:00
CRDT- 2007/02/15 09:00
PHST- 2007/02/15 09:00 [pubmed]
PHST- 2007/06/19 09:00 [medline]
PHST- 2007/02/15 09:00 [entrez]
AID - S0085-2538(15)52455-1 [pii]
AID - 10.1038/sj.ki.5002112 [doi]
PST - ppublish
SO  - Kidney Int. 2007 Apr;71(8):771-7. doi: 10.1038/sj.ki.5002112. Epub 2007 Feb 14.