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Administration of Antivascular Endothelial Growth Factor Receptor 2 Antibody in the Early Follicular Phase Delays Follicular Selection and Development in the Rhesus Monkey

Department of Obstetrics and Gynecology and Center for Reproductive Sciences (R.C.Z., E.X., M.F.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and ImClone Inc. (P.B.), New York, New York 10014

Address all correspondence and requests for reprints to: Dr. Michel Ferin, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032. E-mail: . mf8{at}columbia.edu

Angiogenic factors, including vascular endothelial growth factor (VEGF), are expressed during follicular development. Our objective was to investigate the role of VEGF in the early follicular phase to test whether early cyclic follicle development and selection are angiogenesis-dependent processes. After documentation of two normal ovulatory cycles, female rhesus monkeys (n = 6) received five iv injections of anti-VEGF receptor 2 (anti-VEGF-R2) antibody at 3-d intervals starting on cycle d 2–4. To evaluate nonspecific effects of the treatment antibody, all monkeys also received iv injections of nonspecific humanized mouse IgG, using an identical regimen. Daily measurements of FSH, LH, estradiol, and progesterone were obtained, throughout the entire period, to monitor cyclicity. Administration of anti-VEGF-R2 antibody resulted in a significant decline in mean inhibin B levels [control, 181.0 ± 29.6 (mean ± SE); treatment d 2, 44.5 ± 13.1 pg/ml; P < 0.05]. No decrease was observed after IgG treatment. Anti-VEGF-R2 antibody treatment also delayed the first significant increase in estradiol and lengthened the follicular phase from 10–12 d in the preceding two control cycles to 20–42 d in treatment cycles. FSH and LH concentrations increased significantly, within 24 h after anti-VEGF-R2 antibody treatment, to levels 2–2.5 times over controls. Our results demonstrate that anti-VEGF-R2 antibody therapy in the early follicular phase interferes with the normal development of the cohort of recruited antral follicles. The data clearly indicate that the recruitment-selection process of follicles in the early follicular phase in the nonhuman primate is controlled by VEGF, through the VEGF-R2.

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