A growing body of evidence indicates that the pro-oxidant/anti-oxidant balance inside the ovarian follicle plays an important role in folliculogenesis. Therefore, the aim of the present study was to assess the redox status of follicular fluids collected from different-sized swine follicles. We quantified the most important reactive oxygen species (ROS), namely superoxide anion (O(2)(-)), hydrogen peroxide and hydroperoxides (ROOH); in addition, we examined the activity of the detoxifying enzymes superoxide dismutase, catalase (CAT) and glutathione peroxidase and the total non-enzymatic antioxidant capacity as determined by the ferric-reducing anti-oxidant power assay. Our data demonstrate that oxidative stress does not affect follicle growth because O(2)(-) levels do not change during follicle development, whereas concentrations of H2O2 and ROOH are reduced (P < 0.05). Surprisingly, all non-enzymatic and enzymatic scavengers examined in the present study, except for CAT, demonstrated reduced activity during follicle development (P < 0.05). Taken together, these results suggest that other factors could be involved in ROS detoxification during follicle development.

Experimental evidence documents that nutritional phytoestrogens may interact with reproductive functions but the exact mechanism of action is still controversial. Since quercetin is one of the main flavonoids in livestock nutrition, we evaluated its possible effects on cultured swine granulosa cell proliferation, steroidogenesis, and redox status. Moreover, since angiogenesis is essential for follicle development, the effect of the flavonoid on Vascular Endothelial Growth Factor output by granulosa cells was also taken into account. Our data evidence that quercetin does not affect granulosa cell growth while it inhibits progesterone production and modifies estradiol 17β production in a dose-related manner. Additionally, the flavonoid interferes with the angiogenic process by inhibiting VEGF production as well as by altering redox status. Since steroidogenesis and angiogenesis are strictly involved in follicular development, these findings appear particularly relevant, pointing out a possible negative influence of quercetin on ovarian physiology. Therefore, the possible reproductive impact of the flavonoid should be carefully considered in animal nutrition.

SA appear to be an antiangiogenic natural product by directly suppressing the proliferative effect of VEGF on endothelial cell line: this effect could be mediated by blocking the VEGF-induced Akt activation.

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The rapid, controlled, and cyclical nature of angiogenesis in the ovarian follicle suggests the potential for sex steroids to influence neovascularization. Angiogenesis is regulated by a local balance between the levels of endogenous stimulators and inhibitors. Multiple lines of evidence suggest that estrogens stimulate angiogenesis via effects on endothelial cells. However, it is of outstanding value to investigate the negative control of this process. Since the main estrogen metabolites, 2-hydroxyestradiol and 4-hydroxyestradiol (4-OHE2) have been demonstrated to function as anti-estrogen in several estrogen-dependent organs; the aim of this study was to investigate their potential involvement in the modulation of follicular angiogenesis. Hydroxyestrogens were quantified in swine follicular fluid and their effects were studied on granulosa cell vascular endothelial growth factor (VEGFA) production and tested in an angiogenesis bioassay. Our study documents that these molecules are physiologically present in swine follicular fluid and their concentrations significantly (P!0 . 001) increase during follicle development. Moreover, angiogenesis bioassay revealed that both hydroxyestrogens significantly (P!0 . 001) inhibited new vessel growth. We evidenced that the most potent negative effect is mediated by 4-OHE2. The anti-angiogenic potential of this molecule is also supported by its ability to inhibit (P!0 . 001) VEGFA production by granulosa cells. Increased knowledge in this area is of utmost importance for future therapeutic options to contrast infertility disorders associated with aberrant angiogenesis; this would be also very useful for the treatment of diseases characterized by disregulated angiogenesis and vascular regression.