This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gómez, R. Articles by Pellicer, A. Search for Related Content PubMed PubMed Citation Articles by Gómez, R. Articles by Pellicer, A.

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.

This article has been cited by other articles:

				P. A. Vardhana, M. A. Julius, S. V. Pollak, E. G. Lustbader, R. K. Trousdale, and J. W. Lustbader A Unique Human Chorionic Gonadotropin Antagonist Suppresses Ovarian Hyperstimulation Syndrome in Rats Endocrinology, August 1, 2009; 150(8): 3807 - 3814. [Abstract] [Full Text] [PDF]

				H. Alam, J. Weck, E. Maizels, Y. Park, E. J. Lee, M. Ashcroft, and M. Hunzicker-Dunn Role of the Phosphatidylinositol-3-Kinase and Extracellular Regulated Kinase Pathways in the Induction of Hypoxia-Inducible Factor (HIF)-1 Activity and the HIF-1 Target Vascular Endothelial Growth Factor in Ovarian Granulosa Cells in Response to Follicle-Stimulating Hormone Endocrinology, February 1, 2009; 150(2): 915 - 928. [Abstract] [Full Text] [PDF]

				S. R. Soares, R. Gomez, C. Simon, J. A. Garcia-Velasco, and A. Pellicer Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome Hum. Reprod. Update, April 2, 2008; (2008) dmn008v1. [Abstract] [Full Text] [PDF]

				A. Villasante, A. Pacheco, E. Pau, A. Ruiz, A. Pellicer, and J.A. Garcia-Velasco Soluble vascular endothelial-cadherin levels correlate with clinical and biological aspects of severe ovarian hyperstimulation syndrome Hum. Reprod., March 1, 2008; 23(3): 662 - 667. [Abstract] [Full Text] [PDF]

				C. Alvarez, I. Alonso-Muriel, G. Garcia, J. Crespo, J. Bellver, C. Simon, and A. Pellicer Implantation is apparently unaffected by the dopamine agonist Cabergoline when administered to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction treatment: a pilot study Hum. Reprod., December 1, 2007; 22(12): 3210 - 3214. [Abstract] [Full Text] [PDF]

				P.D. Taylor, H. Wilson, S.G. Hillier, S.J. Wiegand, and H.M. Fraser Effects of inhibition of vascular endothelial growth factor at time of selection on follicular angiogenesis, expansion, development and atresia in the marmoset Mol. Hum. Reprod., October 1, 2007; 13(10): 729 - 736. [Abstract] [Full Text] [PDF]

				M. A. Aboulghar Preventing Ovarian Hyperstimulation Syndrome J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2882 - 2884. [Full Text] [PDF]

				C. Alvarez, L. Marti-Bonmati, E. Novella-Maestre, R. Sanz, R. Gomez, M. Fernandez-Sanchez, C. Simon, and A. Pellicer Dopamine Agonist Cabergoline Reduces Hemoconcentration and Ascites in Hyperstimulated Women Undergoing Assisted Reproduction J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2931 - 2937. [Abstract] [Full Text] [PDF]

				A. Villasante, A. Pacheco, A. Ruiz, A. Pellicer, and J. A. Garcia-Velasco Vascular Endothelial Cadherin Regulates Vascular Permeability: Implications for Ovarian Hyperstimulation Syndrome J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 314 - 321. [Abstract] [Full Text] [PDF]

				R. Gomez, M. Gonzalez-Izquierdo, R. C. Zimmermann, E. Novella-Maestre, I. Alonso-Muriel, J. Sanchez-Criado, J. Remohi, C. Simon, and A. Pellicer Low-Dose Dopamine Agonist Administration Blocks Vascular Endothelial Growth Factor (VEGF)-Mediated Vascular Hyperpermeability without Altering VEGF Receptor 2-Dependent Luteal Angiogenesis in a Rat Ovarian Hyperstimulation Model Endocrinology, November 1, 2006; 147(11): 5400 - 5411. [Abstract] [Full Text] [PDF]

				E. Pau, I. Alonso-Muriel, R. Gomez, E. Novella, A. Ruiz, J. A. Garcia-Velasco, C. Simon, and A. Pellicer Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome Hum. Reprod., June 1, 2006; 21(6): 1453 - 1460. [Abstract] [Full Text] [PDF]

				Y. Kitajima, T. Endo, K. Nagasawa, K. Manase, H. Honnma, T. Baba, T. Hayashi, H. Chiba, N. Sawada, and T. Saito Hyperstimulation and a Gonadotropin-Releasing Hormone Agonist Modulate Ovarian Vascular Permeability by Altering Expression of the Tight Junction Protein Claudin-5 Endocrinology, February 1, 2006; 147(2): 694 - 699. [Abstract] [Full Text] [PDF]

				N. Lambeng, Y. Wallez, C. Rampon, F. Cand, G. Christe, D. Gulino-Debrac, I. Vilgrain, and P. Huber Vascular Endothelial-Cadherin Tyrosine Phosphorylation in Angiogenic and Quiescent Adult Tissues Circ. Res., February 18, 2005; 96(3): 384 - 391. [Abstract] [Full Text] [PDF]

				J. A. Garcia-Velasco and A. Pellicer Reply: coasting acts through down regulation of VEGF gene expression and protein secretion Hum. Reprod., February 1, 2005; 20(2): 575 - 576. [Full Text] [PDF]

				H. M. Fraser, H. Wilson, J. S. Rudge, and S. J. Wiegand Single Injections of Vascular Endothelial Growth Factor Trap Block Ovulation in the Macaque and Produce a Prolonged, Dose-Related Suppression of Ovarian Function J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1114 - 1122. [Abstract] [Full Text] [PDF]

				J.A. Garcia-Velasco, A. Zuniga, A. Pacheco, R. Gomez, C. Simon, J. Remohi, and A. Pellicer Coasting acts through downregulation of VEGF gene expression and protein secretion Hum. Reprod., July 1, 2004; 19(7): 1530 - 1538. [Abstract] [Full Text] [PDF]

				I. Levin, R. Gamzu, Y. Hasson, J.B. Lessing, A. Amit, I. Shapira, S. Berliner, and B. Almog Increased erythrocyte aggregation in ovarian hyperstimulation syndrome: a possible contributing factor in the pathophysiology of this disease Hum. Reprod., May 1, 2004; 19(5): 1076 - 1080. [Abstract] [Full Text] [PDF]

				R Gomez, I Lima, C Simon, and A Pellicer Administration of low-dose LH induces ovulation and prevents vascular hyperpermeability and vascular endothelial growth factor expression in superovulated rats Reproduction, April 1, 2004; 127(4): 483 - 489. [Abstract] [Full Text] [PDF]

				J. Bellver, E. A. Munoz, A. Ballesteros, S. R. Soares, E. Bosch, C. Simon, A. Pellicer, and J. Remohi Intravenous albumin does not prevent moderate-severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study Hum. Reprod., November 1, 2003; 18(11): 2283 - 2288. [Abstract] [Full Text] [PDF]

				J. Bellver, E. Escudero, and A. Pellicer Bilateral partial oophorectomy in the management of severe ovarian hyperstimulation syndrome (OHSS): Ovarian mutilating surgery is not an option in the management of severe OHSS Hum. Reprod., July 1, 2003; 18(7): 1363 - 1367. [Abstract] [Full Text] [PDF]

				R. Gomez, C. Simon, J. Remohi, and A. Pellicer Administration of Moderate and High Doses of Gonadotropins to Female Rats Increases Ovarian Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor-2 Expression that Is Associated to Vascular Hyperpermeability Biol Reprod, June 1, 2003; 68(6): 2164 - 2171. [Abstract] [Full Text] [PDF]