Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome.

Abstract

Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced ( r 2 ϭ 0.73, P Ͻ 0.001). Group IV FF stimulated a 63 Ϯ 4% greater permeability than FF from group I patients ( P Ͻ 0.01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105 Ϯ 87 pg/ml vs. 353 Ϯ 28 pg/ml, P Ͻ 0.05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody.

Inhibition of angiopoietin-1 (ANGPT1) affects vascular integrity in ovarian hyperstimulation syndrome (OHSS)

“…In the present study, we also showed that ZO-1 protein levels in endothelial cells incubated with FF from OHSS patients were lower than those of the control group. These results are consistent with those obtained by Levin et al (1998), who showed that FF from patients suffering from severe OHSS induces destruction of the endothelial ZO-1 TJ protein. We found no changes in ZO-1 levels after the pre-incubation of FF from women at risk of OHSS with the ANGPT1-neutralising antibody.…”

Deciphering Vascular Endothelial Cell Growth Factor/Vascular Permeability Factor Signaling to Vascular Permeability

“…Endothelial Cell Permeability Assay-Assays were performed as described previously (9). Primary cultures of BAEC were seeded onto 0.45-m CM filters (Millipore, Bedford, MA) within plastic inserts; the inserts were placed into 24-well plates, and the cells were grown to confluence over several days.…”

“…This permeability factor also modulates the formation and function of vesiculovascular organelles in venules (5) and the development of EC fenestrations (6). These mechanisms underlie the enhanced vascular permeability seen in response to VPF, which is implicated in the ascites associated with ovarian and other carcinomas (1,7), the pathogenesis of diabetic retinopathy (8), and the ovarian hyperstimulation syndrome (9).…”

“…This results in the dilation of cell tight junctions due to ATP depletion (23). We previously implicated NO as participating in VPF-induced permeability in the pathogenesis of the human ovarian hyperstimulation syndrome (9). In parallel, poorly defined VPF signaling pathways can result in the phosphorylation of TJ proteins that exist in complex, such as zona occludens-1 (ZO-1) or occludin (24).…”

“…Upon phosphorylation, TJ proteins assume abnormal relationships with other members of this complex, thereby creating "leaky" endothelial cell-cell contacts (26,27). Thus, VPF-induced signaling to the cytoskeleton and to associated TJ proteins is potentially important and could present therapeutic targets to prevent vascular pathobiology (7)(8)(9).…”