Regulation of ovarian angiogenesis and apoptosis by GnRH-I analogs.
An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development.
Parborell
Fernanda
F
Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Departamento de Fisiología, Universidad de Buenos Aires, Buenos Aires, Argentina.
Irusta
Griselda
G
Rodríguez Celín
Alejandra
A
Tesone
Marta
M
D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D016729:Leuprolide / Q000008:administration & dosage; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010053:Ovary / Q000098:blood supply / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000096:biosynthesis / Q000187:drug effects; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000187:drug effects
D042683:Angiopoietin-1; D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D007987:Gonadotropin-Releasing Hormone; C057022:iturelix; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D053148:Caspase 3; D016729:Leuprolide