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Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation
Author(s) -
Laschke M W,
Elitzsch A,
Scheuer C,
Holstein J H,
Vollmar B,
Menger M D
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706857
Subject(s) - angiogenesis , neovascularization , in vivo , cell growth , sirolimus , vascular endothelial growth factor , cancer research , biology , pathology , proliferating cell nuclear antigen , endothelial stem cell , ex vivo , pharmacology , medicine , in vitro , vegf receptors , biochemistry , genetics , microbiology and biotechnology
Background and purpose: Rapamycin is a widely used drug with antifungal, immunosuppressant and antiangiogenic effects. Herein, we studied whether immunosuppressive doses of rapamycin are capable of influencing endometriotic lesions. Experimental approach: We tested in vitro the potential of rapamycin to inhibit endothelial cell sprouting using the aortic ring assay and we further studied its effect on the expression of proliferating cell nuclear antigen (PCNA), apoptotic cell death‐associated activated caspase‐3 and vascular endothelial growth factor (VEGF) in cultured endometrial tissue fragments. In addition, we analyzed the drug in vivo after induction of endometriotic lesions by transplanting isolated endometrial fragments into the dorsal skinfold chamber of Syrian golden hamsters. Using intravital fluorescence microscopy, we repetitively analyzed angiogenesis, neovascularization and microcirculatory parameters over a time period of 14 days in rapamycin‐treated animals and DMSO‐treated controls. Key results: Administration of rapamycin significantly reduced the size of the endometriotic lesions. This was associated by inhibition of VEGF‐mediated angiogenesis as indicated by a suppression of endothelial cell sprouting in vitro and a reduction of microvessel density in endometriotic lesions in vivo . Moreover, rapamycin directly inhibited cell proliferation within endometrial tissue, while manifestation of apoptotic cell death remained unaffected. Conclusions and implications: Our data indicate that administration of rapamycin may represent a novel therapeutic approach for an antiangiogenic treatment of endometriosis. British Journal of Pharmacology (2006) 149 , 137–144. doi: 10.1038/sj.bjp.0706857