The role of endothelial cells in the pathogenesis of ovarian hyperstimulation syndrome

Abstract

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of treatment with fertility drugs. Using human lung microvascular endothelial cells (HUMEC-L) as an in-vitro model of OHSS, we have tested the hypothesis that the endothelium is a target of HCG in the pathogenesis of OHSS. Since OHSS is characterized by increased capillary permeability, we have investigated the production and action of vasoactive agents. When HUMEC-L were cultured with high doses of estradiol (E(2)), no significant changes were observed in the secretion of vascular endothelial growth factor (VEGF), interleukin (IL)-6 or IL-1 beta. However, the addition of HCG resulted in a significant increase in the secretion of VEGF and IL-6. Time-course experiments showed that VEGF was secreted within minutes of HCG addition, whereas IL-6 was significantly increased only after 48 h in culture. The secretion of IL-1 beta was unchanged by these hormonal conditions. The presence of HCG receptors was demonstrated in HUMEC-L in basal conditions as well as after the addition of E(2). The expression of VEGF receptors was also investigated. High doses of E(2) were unable to increase the expression of KDR, flt-1 and sfl-t, but the addition of HCG significantly upregulated the KDR concentration in endothelial cells, while no change was observed for flt. Permeability assays demonstrated that while E(2) alone did not change the arrangement of HUMEC-L in vitro, the presence of HCG caused changes in the actin fibres corresponding to increased capillary permeability. Anti-human VEGF antibodies were able to overcome these changes. In conclusion, these experiments show that the endothelium may be a primary target of HCG, causing an acute release of VEGF and a significant increase in IL-6 and resulting in an autocrine-paracrine action that may increase vascular permeability.

Cell junctional proteins in the human corpus luteum: changes during the normal cycle and after HCG treatment

“…This stage of increased permeability may be required to distribute the high amounts of hormones needed to ensure the maintenance of the early pregnancy. Indeed, high doses of HCG significantly increased vascular permeability (Albert et al, 2002;Kitajima et al, 2006), and in rats, this was accompanied by a significant reduction of claudin 5 protein and mRNA expression (Kitajima et al, 2006). It may well be that the reduction of intercellular adhesion by HCG not only allows vascular expansion but also increases vascular permeability.…”

Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome

“…In vitro studies with human lung microvascular endothelial cells have shown that the endothelium contains hCG receptors and responds to this gonadotrophin by releasing VEGF and increasing the amount of VEGFR-2 in the cell surface, suggesting that endothelial cells are involved in the pathogenesis of OHSS as VEGF producers (Albert et al, 2002). Figs 3 and 4 summarize the phases of VEGF expression and increased VP.…”

VEGF antagonist for the prevention of ovarian hyperstimulation syndrome: Current status

“…OHSS is a self-limiting disorder with a broad spectrum of clinical manifestations related to increased capillary permeability and fluid retention brought about by many biochemical mediators, the most important being vascular endothelium growth factor (VEGF). 1 OHSS may be mild, moderate, or severe depending on the various clinical, radiological and laboratory parameters but the clinical impact of the syndrome depends on the variety of symptoms caused by the development of ascites, pleural effusion, hemoconcentration, reduced renal perfusion, and thrombotic complications. This iatrogenic entity can although affects 12e25% of IVF cycles, severe forms of ovarian hyperstimulation syndrome (OHSS) arises in 0.5e5% of assisted reproduction treatment (ART) cycles, and in its most severest form even known to cause maternal death.…”