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.

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

“…Disruption of barrier function has been reported with both decreased and increased claudin-5 expression, indicating complex regulation of the protein within the TJ. Reduced expression of claudin-5 as seen in the present study has been associated with increased permeability in several previous studies (Kirk et al, 2003;Kitajima et al, 2006;Kniesel and Wolburg, 2000;Tsukita and Furuse, 1998). While transfection of claudin-5 into epithelial cells with a low electrical resistance enhances barrier function (Amasheh et al, 2005), overexpression of claudin-5 results in a loss of barrier function and increased permeability and paracellular volume of distribution (Coyne et al, 2003;Kojima et al, 2002;Wang et al, 2003).…”

Regulation of endothelial permeability in the primate corpora lutea: implications for ovarian hyperstimulation syndrome

“…Furthermore, luteal rescue by hCG induced a decrease in Occludin, Claudin 5, and VE-Cadherin in the endothelial cell compartment of human corpora lutea (Groten et al 2006). This observation is in line with studies in rats in which hCG deceased the expression of Claudin 5 mRNA (Kitajima et al 2006), which was associated with increased vascular permeability (Albert et al 2002, Kitajima et al 2006.…”

“…In addition, VEGF originating from the ovary has been assumed to be responsible for the development of pleural effusion (Wang et al 2002). From a therapeutical point of view in patients with OHSS, gonadotropin-releasing hormone agonists can modulate vascular permeability via influencing the expression of the TJ protein Claudin 5 (Kitajima et al 2006). Furthermore, in patients at risk of OHSS, the effect of VEGF on junctional proteins can be also inhibited by dopamine agonists, thus decreasing vascular permeability (Gomez et al 2011, Kumar et al 2011, Soares 2012.…”

How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries

“…High estrogen concentrations significantly increased ovarian perfusion and vessel endothelial area in a rat model of ovarian hyperstimulation, and this effect was significantly and dosedependently inhibited by administration of a GnRH agonist [58]. The decreased utero-ovarian perfusion induced by the GnRH agonist may result in a lower total cumulative exposure of the ovaries to the chemotherapeutic agents as compared with a "control" patient, in a normoestrogenic milieu, thus resulting in less gonadotoxicity.…”

“…Another possible explanatory mechanism for the beneficial effect of GnRH agonists on decreasing chemotherapy-associated gonadotoxicity is the decrease in utero-ovarian perfusion resulting from the hypoestrogenic state generated by pituitary-gonadal desensitization [57,58]. High estrogen concentrations significantly increased ovarian perfusion and vessel endothelial area in a rat model of ovarian hyperstimulation, and this effect was significantly and dosedependently inhibited by administration of a GnRH agonist [58].…”