Effect of Antiprogesterone RU486 on VEGF Expression and Blood Vessel Remodeling on Ovarian Follicles before Ovulation

Abstract

BackgroundThe success of ovarian follicle growth and ovulation is strictly related to the development of an adequate blood vessel network required to sustain the proliferative and endocrine functions of the follicular cells. Even if the Vascular Endothelial Growth Factor (VEGF) drives angiogenesis before ovulation, the local role exerted by Progesterone (P4) remains to be clarified, in particular when its concentration rapidly increases before ovulation.AimThis in vivo study was designed to clarify the effect promoted by a P4 receptor antagonist, RU486, on VEGF expression and follicular angiogenesis before ovulation, in particular, during the transition from pre to periovulatory follicles induced by human Chorionic Gonadotropins (hCG) administration.Material and MethodsPreovulatory follicle growth and ovulation were pharmacologically induced in prepubertal gilts by combining equine Chorionic Gonadotropins (eCG) and hCG used in the presence or absence of RU486. The effects on VEGF expression were analyzed using biochemical and immunohistochemical studies, either on granulosa or on theca layers of follicles isolated few hours before ovulation. This angiogenic factor was also correlated to follicular morphology and to blood vessels architecture.Results and ConclusionsVEGF production, blood vessel network and follicle remodeling were impaired by RU486 treatment, even if the cause-effect correlation remains to be clarified. The P4 antagonist strongly down-regulated theca VEGF expression, thus, preventing most of the angiogenic follicle response induced by hCG. RU486-treated follicles displayed a reduced vascular area, a lower rate of endothelial cell proliferation and a reduced recruitment of perivascular mural cells. These data provide important insights on the biological role of RU486 and, indirectly, on steroid hormones during periovulatory follicular phase. In addition, an in vivo model is proposed to evaluate how periovulatory follicular angiogenesis may affect the functionality of the corpus luteum (CL) and the success of pregnancy.

Cellular and molecular maturation in fetal and adult ovine calcaneal tendons

“…Intriguingly, only in mid-fetal tendons, VEGF-secreting cells were organised in islets that were positioned close to blood vessels. The strict correlation between VEGF and blood vessels is well documented in several tissue models (Martelli et al 2009;Barboni et al 2012b;Mauro et al 2014). This research confirms that VEGF is a trophic supply for blood vessels.…”

Anti-Ovarian Vessels Antibodies in P. aeruginosa Rabbit Hyper Immune Sera, an Immunohistochemical Study

“…None the less anti angiogenic agents including the monoclonal antibody bevacizumab with anti-VEGF activity has been used in phase II trial in recurrent epithelial ovarian cancer [20][21]. Furthermore, the overian blood vessels are target for antibody [22][23].…”

Pigment epithelium-derived factor regulation by human chorionic gonadotropin in granulosa cells

“…In the current study, we illustrate the delicate physiological angiogenic balance in the ovary. VEGF, a key regulator of ovarian vasculature (Mauro et al 2014) is upregulated by LH/hCG in granulosa cells (Herr et al 2013). The signal transduction that governs hCGinduced VEGF biosynthesis is well documented and is known to be mediated by several factors as PKC (Sriraman et al 2008), PKA (van den Driesche et al 2008) and AREG (Karakida et al 2011)).…”

“…If pregnancy does not occur, ovarian angiogenesis regresses (Reynolds & Redmer 1998). Vascular endothelial growth factor (VEGF) is a key regulator of ovarian vasculature (Mauro et al 2014) upregulated by LH in granulosa cells (Herr et al 2013).…”