Vascular mechanisms in ovulation

Abstract: Ovulation is a unique biological process, which involves the degradation and rupture of healthy tissue of the ovarian follicle and the extrusion of the oocyte. This process is initiated by the preovulatory surge of luteinizing hormone (LH), which leads to the up-regulation of various intraovarian mediators. These ovulatory mediators, such as eicosanoids, nitric oxide (NO), angiotensin (ANG) II and cytokines, function co-operatively to promote subsequent structural and mechanical changes in the ovary. Prominent alterations in the ovarian vasculature occur during the ovulatory period and the resulting increase in ovarian blood flow (OBF) and permeability may be of importance for the ovulation. The aims of the present study were to evaluate the contributions of two of the major vasoactive substances in the ovary, NO and ANG II, in ovulation of the rat, and also to characterize the changes in the OBF and the ovarian vascular permeability during this period.Expression of two isoforms of NO synthase (NOS), the constitutively expressed endothelial NOS (eNOS) and the inducible NOS (iNOS), has been demonstrated in the periovulatory rat ovary. A nonselective NOS inhibitor suppressed ovulation rate in the in vitro perfused rat ovary, while an iNOS selective antagonist was without effect. This indicates the relative importance of eNOS over iNOS in the ovulatory process. Administration of exogenous NO did not affect the ovulation rate, indicating that the ovarian local production of NO is sufficient for the full ovulatory response. Intravenous administration of a nonselective NOS inhibitor caused only a transient decrease in OBF, while local ovarian administration of the same inhibitor resulted in a persistent decline in OBF. The immediate increase in OBF after the gonadotropin stimulation also disappeared in the presence of the NOS inhibitor. These findings indicate that OBF is positively regulated by the ovarian local NO system and that there exists blood-sparing mechanisms against the systemic NOS antagonism. A complete renin angiotensin system (RAS) has been localized to the ovary and ANG II may be involved in the ovulatory process through the activation of either or both of the type 1 (AT1) or the type 2 (AT2) receptors. In the rat ovary, AT2 is expressed solely in the atretic follicles and the selective antagonist to this receptor did not affect ovulation. The AT1 selective inhibitor also failed to affect ovulation, but the combined treatment with the AT1 and the AT2 receptor antagonists significantly reduced ovulation number. Studies by laser Doppler flowmetry revealed that the AT1 and the AT2 receptors negatively modulate OBF in different manners and that under physiological conditions, AT2 is the major receptor involved. Increased ovarian microvascular permeability after the LH surge may be of importance for the ovulatory process. The size-selective properties of the rat ovarian vasculature during the preovulatory period were quantified by using FITC-Ficoll tracer and applying the sieving data to the two-pore model. After stimulation with hCG, there was a dramatic increase in capillary permeability secondary to an increased number of large pores mimicking an inflammatory reaction.In summary, these studies suggest that the marked changes in OBF and ovarian vascular permeability are essential for the ovulatory process and that ovarian NO and ANG II systems may facilitate ovulation through modulation of these ovarian vascular mechanisms.