Ovary

Effect of a Vascular Endothelial Growth Factor (VEGF) Inhibitory Treatment on the Folliculogenesis and Ovarian Apoptosis in Gonadotropin-Treated Prepubertal Rats

Abstract
In the present study, we investigated whether VEGFA plays a critical intraovarian survival role for gonadotropin-dependent folliculogenesis. The effect of intrabursal administration of a VEGFA antagonist on follicular development, apoptosis, and the levels of pro and antiapoptotic proteins of BCL2 family members (BAX, BCL2 and BCL2L1), as well as of TNFRSF6 and FASLG, was examined. To inhibit VEGFA, a soluble FLT1/Fc Chimera (Trap) was administered to prepubertal eCG-treated rats. Injection of 0.5 ?[mu]g Trap/ovary did not change the number of preantral (PF) or early antral follicles (EAF); however, it significantly decreased the number of periovulatory follicles 48 h after surgery, and significantly increased the number of atretic follicles. No significant differences were found in any stage of the follicles either 12 or 24 h after injection. Cells undergoing DNA fragmentation were quantified by performing TUNEL on ovarian sections. Trap treatment caused a two-fold increase in the number of apoptotic cells in EAF. DNA isolated from antral follicles incubated 24 h exhibited the typical apoptotic DNA pattern. Follicles obtained from Trap-treated ovaries showed a significant increase in the spontaneous onset of apoptotic DNA fragmentation. The injection of Trap significantly increased the levels of BAX and decreased the levels of BCL2 protein. The ratio of BCL2L1L/BCL2L1s was significantly diminished in follicles obtained from ovaries treated with Trap. No changes in the levels of TNFRSF6 or FASLG were observed after treatment. We concluded that the local inhibition of VEGFA activity appears to produce an increase in ovarian apoptosis through an imbalance among the BCL2 family members, thus leading a larger number of follicles to atresia.

Key words: Female Reproductive Tract • Ovary • Apoptosis • Follicular development • Growth factors

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