Hyperstimulation and a gonadotropin-releasing hormone agonist modulate ovarian vascular permeability by altering expression of the tight junction protein claudin-5.
ABSTRACT We investigated the mechanism by which a GnRH agonist (GnRHa) affects ovarian vascularity, vascular permeability, and expression of the tight junction protein claudin-5 in a rat model of ovarian hyperstimulation syndrome (OHSS). Hyperstimulated rats received excessive doses of pregnant mare serum gonadotropin (PMSG; 50 IU/d) for 4 consecutive days, from d 25 to 28 of life, followed by 25 IU human chorionic gonadotropin (hCG) on d 29. Control rats received 10 IU PMSG on d 27 of life, followed by 10 IU hCG on d 29. GnRHa (leuprolide 100 microg/kg.d) was administered to some hyperstimulated rats either on d 29 and 30 (short-term GnRHa treatment) or from d 25 to 30 (long-term GnRHa treatment). Ovarian vascular density (vessels per 10 mm(2)) and vessel endothelial area (percent) were assessed by immunohistochemical analysis of the distribution of von Willebrand factor, whereas vascular permeability was evaluated based on leakage of Evans blue. High doses of PMSG and hCG significantly increased ovarian weight, vascular permeability, vascular density, and the vessel endothelial area and significantly reduced expression of claudin-5 protein and mRNA. All of these effects were significantly and dose-dependently inhibited by administration of GnRHa. This suggests that reduced expression of claudin-5 plays a crucial role in the increased ovarian vascular permeability seen in OHSS and that its expression can be modulated by GnRHa treatment. Indeed, preventing redistribution of tight junction proteins in endothelial cells and the resultant loss of endothelial barrier architecture might be the key to protecting patients against massive extravascular fluid accumulation in cases of OHSS.
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ABSTRACT: The development of the human corpus luteum (yellow body) is dictated by a strictly controlled system of mutually communicating cells, the luteal steroid hormone-producing cells and endothelial cells. This cell-to-cell communication facilitates control of neoangiogenesis which is a prerequisite for the development of the corpus luteum and its function, the rapid release of large amounts of progesterone into the blood-vascular system. Preconditions for this process are the hormonal regulation of endothelial cell proliferation as well as of vascular permeability through LH and hCG. The morphological correlates of endothelial permeability are cell-to-cell adhesion molecules such as adherens junctions (AJ) and tight junctions (TJ) that open and close the gaps between mutually interacting, neighbouring endothelial cells like a "zip fastener". Various types of cell adhesion molecules have been detected in the corpus luteum such as occludin, claudin 1 and claudin 5 as well as VE-cadherin. It may be assumed that the regulation of AJ and TJ proteins is of particular importance for the permeability and thus for the function of the corpus luteum in early pregnancy since hCG treatment leads to a down-regulation of cell adhesion molecules in the luteal vessels. This effect is apparently mediated by VEGF. From a functional point of view, the hCG-dependent and VEGF-mediated down-regulation of cell adhesion molecules leads to a reduced transmissibility of cell-to-cell contacts and thus to an increased endothelial permeability. In this process the various cell adhesion molecules are not only directly regulated by VEGF but they also mutually interact and thus influence one another.Geburtshilfe und Frauenheilkunde 11/2013; 73(11):1107-1111. · 0.85 Impact Factor
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ABSTRACT: In assisted reproduction cycles, gonadotropins are administered to obtain a greater number of oocytes. A majority of patients do not have an adverse response; however, approximately 3-6% develop ovarian hyperstimulation syndrome (OHSS). Metformin reduces the risk of OHSS but little is known about the possible effects and mechanisms of action involved. To evaluate whether metformin attenuates some of the ovarian adverse effects caused by OHSS and to study the mechanisms involved. A rat OHSS model was used to investigate the effects of metformin administration. Ovarian histology and follicle counting were performed in ovarian sections stained with Masson trichrome. Vascular permeability was measured by the release of intravenously injected Evans Blue dye (EB). VEGF levels were measured by commercially immunosorbent assay kit. COX-2 protein expression was evaluated by western blot and NOS levels were analyses by immunohistochemistry. Animals of the OHSS group showed similar physiopathology characteristics to the human syndrome: increased body weight, elevated progesterone and estradiol levels (P<0.001), increased number of corpora lutea (P<0.001), higher ovarian VEGF levels and vascular permeability (P<0.001 and P<0.01); and treatment with metformin prevented this effect (OHSS+M group; P<0.05). The vasoactive factors: COX-2 and NOS were increased in the ovaries of the OHSS group (P<0.05 and P<0.01) and metformin normalized their expression (P<0.05); suggesting that metformin has a role preventing the increased in vascular permeability caused by the syndrome. Metformin has a beneficial effect preventing OHSS by reducing the increase in: body weight, circulating progesterone and estradiol and vascular permeability. These effects of metformin are mediated by inhibiting the increased of the vasoactive molecules: VEGF, COX-2 and partially NOS. Molecules that are increased in OHSS and are responsible for a variety of the symptoms related to OHSS.Journal of Ovarian Research 09/2013; 6(1):62. · 2.43 Impact Factor
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ABSTRACT: The relationship between human chorionic gonadotropin and ovarian hyperstimulation syndrome (OHSS) is partially mediated by vascular endothelial growth factor A (VEGF). The aim of this study was to investigate the effects of VEGF inhibition on the development of corpora lutea (CL) and cystic structures, steroidogenesis, apoptosis, cell proliferation, endothelial cell area, VEGF receptors (KDR and Flt-1), claudin-5 and occludin levels in ovaries from an OHSS rat model. The VEGF inhibitor used (VEGF receptor-1 (FLT-1)/Fc chimera, TRAP) decreased the concentrations of progesterone and estradiol as well as the percentage of CL and cystic structures in OHSS rats, and increased apoptosis in CL. Endothelial cell area in CL and KDR expression and its phosphorylation were increased, whereas claudin-5 and occludin levels were decreased in the OHSS compared to the control TRAP reversed these parameters. Our findings indicate that VEGF inhibition prevents the early onset of OHSS and decreases its severity in rats.The Journal of steroid biochemistry and molecular biology. 08/2014;