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.

Vascular Endothelial Growth Factor and Angiogenesis

“…The major components in the development of the syndrome are ovarian enlargement and increased vascular permeability. The latter leads to the extravasation of protein-rich fluid from the intravascular space into the peritoneal, pleural, and pericardial cavities, edema, and hypovolemia, leading to hypotension and anuria in the most severe cases (Levin et al, 1998). The syndrome is more likely to occur when a good ovarian response to gonadotrophic hormones is seen, with large numbers of stimulated follicles and an increase in serum estradiol.…”

VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain

“…Some effects of exogenous VEGF on endothelial cells in vitro are partially attributed to the generation of nitric oxide (NO) from these cells (69,70). In vivo, NO increases CBF (71).…”

GnRH analogues: applications in assisted reproductive techniques

“…VEGF is important in the development and maintenance of vasculature in the developing tissue beds of the CL and decidua. However, it has also been implicated in the pathophysiology of OHSS, when it is overexpressed and increasingly bioavailable (51). The consequences can be severe with intravascular volume loss and extravascular fluid accumulation leading to thromboembolic disease, ascites, renal and cardiorespiratory compromise.…”