Effect of a vascular endothelial growth factor (VEGF) inhibitory treatment on

ABRAMOVICH D, PARBORELL F, TESONE M.

BIOLOGY OF REPRODUCTION

Año: 2006 vol. 75 p. 434 - 441

0006-3363

In the present study, we investigated whether vascular endothelial growth factorA (VEGFA) plays a critical intraovarian survival role in gonadotropin-dependentfolliculogenesis. The effect of an intrabursal administration of a VEGFAantagonist on follicular development, apoptosis, and levels of pro- andantiapoptotic proteins of BCL2 family members (BAX, BCL2, and BCL2L1), as wellas of TNFRSF6 (also known as FAS) and FAS ligand (FASLG), was examined. Toinhibit VEGFA, a soluble FLT1/Fc Chimera (Trap) was administered to prepubertaleCG-treated rats. Injection of 0.5 mug of Trap per ovary did not change thenumber of preantral follicles (PFs) or early antral follicles (EAFs); however,it significantly decreased the number of periovulatory follicles 48 h aftersurgery and significantly increased the number of atretic follicles. Nosignificant differences were found in any stage of the follicles either 12 or 24h after injection. Cells undergoing DNA fragmentation were quantified byperforming TUNEL on ovarian sections. Trap treatment caused a twofold increasein the number of apoptotic cells in EAFs. DNA isolated from antral folliclesincubated for 24 h exhibited the typical apoptotic DNA pattern. Folliclesobtained from Trap-treated ovaries showed a significant increase in thespontaneous onset of apoptotic DNA fragmentation. The injection of Trapsignificantly increased the levels of BAX and decreased the levels of BCL2protein. The ratio of BCL2L1L:BCL2L1s was significantly diminished in folliclesobtained from ovaries treated with Trap. No changes in the levels of TNFRSF6 orFASLG were observed after treatment. We concluded that the local inhibition ofVEGFA activity appears to produce an increase in ovarian apoptosis through animbalance among the BCL2 family members, thus leading a larger number offollicles to atresia.