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Vascular Endothelial Growth Factor Receptor-2 Activation Induces Vascular Permeability in Hyperstimulated Rats, and this Effect Is Prevented by Receptor Blockade

Fundación IVI para el Estudio de la Reproducción (R.G., C.S., J.R., A.P.); Department of Pediatrics, Obstetrics, and Gynecology (C.S., J.R., A.P.), Valencia University School of Medicine; and Department of Obstetrics and Gynecology, Hospital Universitario Dr. Peset (A.P.), Valencia 46020, Spain

Address all correspondence and requests for reprints to: Antonio Pellicer, M.D., FIVIER, Guardia Civil 23, esc 6. pta 7, Valencia 46020, Spain. E-mail: apellicer{at}interbook.net.

The existence of a vasoactive molecule released in response to hCG is believed to be the main feature in the development of ovarian hyperstimulation syndrome (OHSS) in women, and vascular endothelial growth factor (VEGF) is the main candidate as the human chorionic gonadotropin (hCG) mediator. This study was conducted to investigate the role of VEGF in increasing vascular permeability (VP) in vivo, a characteristic of OHSS. We analyzed the source and specific isoforms of VEGF involved and developed strategies to reverse increased VP in hyperstimulated rats targeting the VEGF system.

Ovarian hyperstimulation was induced with pregnant mare’s serum gonadotropin, or pregnant mare’s serum gonadotropin plus hCG. Time-course experiments analyzed VP and the expression of whole VEGF mRNA in the mesentery and the ovaries. VP and ovarian mRNA VEGF expression increased to peak values after 48 h. No significant change in expression was observed in the mesentery. To further prove the ovarian origin of VEGF, we showed that VP was not altered when ovariectomized rats were treated with gonadotropins. The ovary expressed VEGF₁₂₀ and VEGF₁₆₄ isoforms. Immunohistochemistry showed VEGF in granulosa and zona pellucida of preovulatory and atretic follicles and in granulosa-lutein and endothelial cells of whole corpus luteum.

A specific VEGF receptor-2 inhibitor (SU5416) was administered in three different protocols: on a daily basis, every 48 h, or two injections after hCG. Increased VP was reversed when SU5416 was administered every 48 h or two injections after hCG. These results show that the ovary is the main source of VEGF₁₂₀ and VEGF₁₆₄, which act through the VEGF receptor-2 to increase VP, and provide new insights into the prevention of OHSS.

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