Ovarian hyperstimulation syndrome (OHSS) is a severe complication arising from controlled ovarian stimulation treatment. This iatrogenic condition is potentially lethal and occurs in 0.3-5% of stimulated ovarian cycles. hCG exacerbates OHSS. The pathophysiology of OHSS is still unknown; therefore, treatment regimens are aimed at ameliorating symptoms. Prominent features of OHSS are an elevated risk of thromboembolism due to enhanced production of von Willebrand factor by endothelial cells and ascites, or pulmonary edema due to increased vascular permeability followed by third space fluid accumulation. Both of these sequelae can be evoked by vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF). High concentrations of VEGF/VPF have been demonstrated in ascitic fluid from patients with OHSS, but the source of VEGF/VPF in these patients remained unidentified. Here we report that the messenger ribonucleic acid expression of VEGF/VPF in human luteinized granulosa cells (GCs) is dose and time dependently enhanced by hCG in vitro. Furthermore, VEGF/VPF proteins are produced by GCs. Our results suggest that the effects of hCG on the development and course of OHSS may be mediated by the production of VEGF/VPF by GCs.
The zona pellucida (ZP) is a glycoprotein matrix surrounding mammalian oocytes. Upon fertilization, ZP hardening prevents sperm from binding to and penetrating the ZP. Here, we report that targeted gene deletion of the liver-derived plasma protein fetuin-B causes premature ZP hardening and, consequently, female infertility. Transplanting fetuin-B-deficient ovaries into wild-type recipients restores fertility, indicating that plasma fetuin-B is necessary and sufficient for fertilization. In vitro fertilization of oocytes from fetuin-B-deficient mice only worked after rendering the ZP penetrable by laser perforation. Mechanistically, fetuin-B sustains fertility by inhibiting ovastacin, a cortical granula protease known to trigger ZP hardening. Thus, plasma fetuin-B is necessary to restrain protease activity and thereby maintain ZP permeability until after gamete fusion. These results also show that premature ZP hardening can cause infertility in mice.
Anorexia nervosa (AN) is an often chronic, difficult to treat illness that leads to brain volume reductions in gray and white matter. The underlying pathophysiology is poorly understood, despite its potential importance in explaining the neuropsychological deficits and clinical symptoms associated with the illness. We used the activity-based anorexia model (ABA), which includes food reduction and running wheel access in female rats to study brain changes after starvation and refeeding. Longitudinal animal MRI and post-mortem brain sections confirmed a reduction in the mean brain volumes of ABA animals compared to controls. In addition, the mean number of astrocytes was reduced by over 50% in the cerebral cortex and corpus callosum, while the mean number of neurons was unchanged. Furthermore, mean astrocytic GFAP mRNA expression was similarly reduced in the ABA animals, as was the mean cell proliferation rate, whereas the mean apoptosis rate did not increase. After refeeding, the starvation-induced effects were almost completely reversed. The observation of the astrocyte reduction in our AN animal model is an important new finding that could help explain starvation-induced neuropsychological changes in patients with AN. Astrocyte-targeted research and interventions could become a new focus for both AN research and therapy.
Volumetric brain changes in ABA animals mirror those in human AN patients. These alterations are associated with a reduction of GFAP-positive astrocytes as well as GFAP expression. Reduced astrocyte functioning could help explain neuronal dysfunctions leading to symptoms of rigidity and impaired learning. Astrocyte loss could constitute a new research target for understanding and treating semi-starvation and AN.
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