HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hazzard, T. M. Articles by Stouffer, R. L. Search for Related Content PubMed PubMed Citation Articles by Hazzard, T. M. Articles by Stouffer, R. L. Agricola Articles by Hazzard, T. M. Articles by Stouffer, R. L.

Injection of Soluble Vascular Endothelial Growth Factor Receptor 1 into the Preovulatory Follicle Disrupts Ovulation and Subsequent Luteal Function in Rhesus Monkeys¹

^a Division of Reproductive Sciences, Oregon National Primate Research Center/Oregon Health & Science University, Beaverton, Oregon 97006 ^b Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97201

Remarkable changes in vascular permeability and neovascularization occur within the ovulatory, luteinizing follicle. To evaluate the importance of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in periovulatory events, sequential experiments were designed in which vehicle (PBS/0.1% BSA; controls, n = 13) or a low dose (1.5 µg; n = 4) or a high dose (7.5 µg; n = 4) of a VEGF antagonist, soluble VEGF receptor 1 (sVEGFR1) chimera, was injected directly into the preovulatory follicle of rhesus monkeys the day before (Day -1) or the day of (Day 0) the midcycle LH surge during spontaneous menstrual cycles. After vehicle injection, animals typically exhibited patterns and levels of serum progesterone (P₄) that were comparable to those of untreated animals in our colony. Following low-dose sVEGFR1 injection, serum P₄ levels were diminished in two of four animals from the early to midluteal phase, but were similar to vehicle controls thereafter. In contrast, high-dose sVEGFR1 injection decreased serum P₄ levels throughout the luteal phase compared with levels in controls (P < 0.05), but it did not cause premature menstruation. Control follicles displayed indices of rupture (protruding stigmata) and luteinization. However, sVEGFR1-injected follicles exhibited signs of distension (torn surface epithelium/tunica albuginea) and luteinization, but not necessarily timely ovulation. Histological evaluation of serial sections from ovaries removed on Day 3 after treatment revealed that all (n = 3) vehicle-injected follicles ovulated, whereas half (n = 3 of 6) the sVEGFR1-injected follicles failed to ovulate and still contained an oocyte in the antrum. No appreciable differences were apparent between treatment groups in numbers of cells in luteal tissue (Day 3 or 6 after treatment) that stained positive for immunochemical or histochemical markers of proliferative (Ki67), endothelial (platelet endothelial cell adhesion molecule 1), and steroidogenic (3ß-hydroxysteroid dehydrogenase) cells. However, there was a dose-dependent increase (P < 0.05) in extracellular space in the corpus luteum by midluteal phase in sVEGFR1-treated animals. The data suggest that acute exposure to a VEGF antagonist can impair ovulation, and the subsequent development and functional capacity of the primate corpus luteum. The results are consistent with a critical role for VEGF in normal ovarian function during the periovulatory interval in primates.

¹ This work was supported by the National Institute of Child Health and Human Development through cooperative agreement U54(HD18185) as part of the Specialized Cooperative Centers Program in Reproduction Research; by grant RF96020 from the World Health Organization/Rockefeller Foundation; and by grants HD22408, HD07133, and RR00163 from the National Institutes of Health.

² Correspondence: Richard L. Stouffer, Oregon National Primate Research Center, 505 N.W. 185th Avenue, Beaverton, OR 97006. FAX: 503 690 5563; stouffri{at}ohsu.edu

This article has been cited by other articles:

				S. van den Driesche, M. Myers, E. Gay, K. J. Thong, and W. C. Duncan HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum Mol. Hum. Reprod., August 1, 2008; 14(8): 455 - 464. [Abstract] [Full Text] [PDF]

				T. Shimizu, K. Iijima, K. Miyabayashi, Y. Ogawa, H. Miyazaki, H. Sasada, and E. Sato Effect of direct ovarian injection of vascular endothelial growth factor gene fragments on follicular development in immature female rats Reproduction, November 1, 2007; 134(5): 677 - 682. [Abstract] [Full Text] [PDF]

				J. Xu, F. Xu, J. D. Hennebold, T. A. Molskness, and R. L. Stouffer Expression and Role of the Corticotropin-Releasing Hormone/Urocortin-Receptor-Binding Protein System in the Primate Corpus Luteum during the Menstrual Cycle Endocrinology, November 1, 2007; 148(11): 5385 - 5395. [Abstract] [Full Text] [PDF]

				D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]

				L. S. Sleer and C. C. Taylor Platelet-Derived Growth Factors and Receptors in the Rat Corpus Luteum: Localization and Identification of an Effect on Luteogenesis Biol Reprod, March 1, 2007; 76(3): 391 - 400. [Abstract] [Full Text] [PDF]

				D. Abramovich, F. Parborell, and M. Tesone Effect of a Vascular Endothelial Growth Factor (VEGF) Inhibitory Treatment on the Folliculogenesis and Ovarian Apoptosis in Gonadotropin-Treated Prepubertal Rats Biol Reprod, September 1, 2006; 75(3): 434 - 441. [Abstract] [Full Text] [PDF]

				N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M. Fauser The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization Endocr. Rev., April 1, 2006; 27(2): 170 - 207. [Abstract] [Full Text] [PDF]

				M. Tesone, R. L. Stouffer, S. M. Borman, J. D. Hennebold, and T. A. Molskness Vascular Endothelial Growth Factor (VEGF) Production by the Monkey Corpus Luteum During the Menstrual Cycle: Isoform-Selective Messenger RNA Expression In Vivo and Hypoxia-Regulated Protein Secretion In Vitro Biol Reprod, November 1, 2005; 73(5): 927 - 934. [Abstract] [Full Text] [PDF]

				H. M. Fraser, H. Wilson, K. D. Morris, I. Swanston, and S. J. Wiegand Vascular Endothelial Growth Factor Trap Suppresses Ovarian Function at All Stages of the Luteal Phase in the Macaque J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5811 - 5818. [Abstract] [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]

				N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [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]

				J. Greenaway, K. Connor, H. G. Pedersen, B. L. Coomber, J. LaMarre, and J. Petrik Vascular Endothelial Growth Factor and Its Receptor, Flk-1/KDR, Are Cytoprotective in the Extravascular Compartment of the Ovarian Follicle Endocrinology, June 1, 2004; 145(6): 2896 - 2905. [Abstract] [Full Text] [PDF]

				T.A. Molskness, R.L. Stouffer, K.A. Burry, M.J. Gorrill, D.M. Lee, and P.E. Patton Circulating levels of free and total vascular endothelial growth factor (VEGF)-A, soluble VEGF receptors-1 and -2, and angiogenin during ovarian stimulation in non-human primates and women Hum. Reprod., April 1, 2004; 19(4): 822 - 830. [Abstract] [Full Text] [PDF]

				T. Shimizu, J.-Y. Jiang, K. Iijima, K. Miyabayashi, Y. Ogawa, H. Sasada, and E. Sato Induction of Follicular Development by Direct Single Injection of Vascular Endothelial Growth Factor Gene Fragments into the Ovary of Miniature Gilts Biol Reprod, October 1, 2003; 69(4): 1388 - 1393. [Abstract] [Full Text] [PDF]

				A. Martoriati, G. Duchamp, and N. Gerard In Vivo Effect of Epidermal Growth Factor, Interleukin-1{beta}, and Interleukin-1RA on Equine Preovulatory Follicles Biol Reprod, May 1, 2003; 68(5): 1748 - 1754. [Abstract] [Full Text] [PDF]

				J. C. Benedict, K. P. Miller, T.-M. Lin, C. Greenfeld, J. K. Babus, R. E. Peterson, and J. A. Flaws Aryl Hydrocarbon Receptor Regulates Growth, But Not Atresia, of Mouse Preantral and Antral Follicles Biol Reprod, May 1, 2003; 68(5): 1511 - 1517. [Abstract] [Full Text] [PDF]

				J.C. Martinez-Chequer, R.L. Stouffer, T.M. Hazzard, P.E. Patton, and T.A. Molskness Insulin-Like Growth Factors-1 and -2, but not Hypoxia, Synergize with Gonadotropin Hormone to Promote Vascular Endothelial Growth Factor-A Secretion by Monkey Granulosa Cells from Preovulatory Follicles Biol Reprod, April 1, 2003; 68(4): 1112 - 1118. [Abstract] [Full Text] [PDF]