CONICET | Buscador de Institutos y Recursos Humanos

Vascular Endothelial Growth Factor A (VEGF) is the main angiogenic factor involved in proliferation, migration and endothelial cell permeability. While VEGF is the major initiator of angiogenesis, the formation and differentiation of a functionally mature vascular network requires the coordinated action of various factors. These include angiopoietins (ANGPT), which act via the tyrosine kinase receptor, Tie-2. ANGPT1 is required for the recruitment of periendothelial cells that lead to the maturation and stabilization of newly developed capillaries. On the other hand, ANGPT2 acts as a receptor antagonist destabilizing the blood vessels. PCOS is the major cause of infertility among women; its main features are endocrine, metabolic and reproductive alterations. Patients have increased levels of VEGF in serum due to the high ovarian production. Given the implication of the angiogenesis in this syndrome, we investigated in a PCOS rat model the effect of VEGF inhibition on follicular development and the levels of ovarian ANGPT1, ANGPT2 and Tie2. Prepubertal rats were injected for 15 days with dehydroepiandrosterone (DHEA, 6 mg/100 g body weight) to induce PCOS. Control group received vehicle. PCOS rats were divides in two groups. One group was injected under the bursa of the ovary with a VEGF inhibitor (Trap) 48 h before sacrifice (PCOS Trap). The other group was injected under the bursa with vehicle (PCOS control). The ovaries were removed; one was stained with H&E or processed for smooth muscle cell alpha actin (SMC actin) immunohistochemistry to study blood vessel stability. Proteins were extracted from the other ovary to perform western blot studies for ANGPTs and Tie2. Histological studies confirmed the presence of follicular cysts, many atretic follicles and a very low amount of corpora lutea in the ovaries from the PCOS group correlated with a significant decrease in circulating progesterone levels. There was an increase in the percentage of primary follicles in the PCOS rats that was reversed with Trap. Besides, Trap decreased the percentage of preantral follicles and the percentage of cysts without changes in atretic follicles. There were no changes in ovarian SMC actin immunostaining between control and PCOS group. However, Trap decreased significantly SMC actin expression. In addition, there was a significant increase in the levels of ANGPT1 and Tie2 and a significant decrease in the levels of ANGPT2 in the PCOS ovaries compared to controls. None of these changes were reversed with Trap treatment. These results suggest that the treatment with a VEGF inhibitor improves follicular development and decreases ovarian cysts formation in a rat model of PCOS. Furthermore, changes in the levels of ANGPTs and their receptor Tie2 could be involved in the PCOS patophysiology. Supported by: ANPCYT (BID 1201 OC-AR PICT 99:05-06384) and CONICET (PIP 1223)