Research has implicated two factors which act specifically on endothelial cells as key players in the development and maintenance of the vasculature vascular endothelial growth factors (VEGF), and angiopoietins (ANG). Studies were designed to determine (1) if VEGF or ANG expression increases in the primate follicle during the periovulatory interval in vivo, and whether their expression is regulated by the gonadotropin surge or local (i.e., steroids) factors, and (2) if VEGF or ANG is expressed in the primate corpus luteum throughout its lifespan in the menstrual cycle. First, female rhesus monkeys received gonadotropins to promote the development of multiple preovulatory follicles. Then animals received an ovulatory gonadotropin (hCG) bolus alone or with the steroid synthesis inhibitor Trilostane, with and without progestin replacement. Follicular fluid and granulosa cells were collected before (0 hr) and 12, 24, or 36 hr after administering the hCG bolus. VEG F, ANG-1 and ANG-2 mRNAs were detected in granulosa cells at all timepoints. Whereas no significant changes in VEGF or ANG-2 mRNAs were observed, ANG-1 mRNA decreased from 0 to 12 hrs and then increased 30-fold by 36 hrs. Steroid ablation prevented the 36 hr rise in ANG-1 mRNA, which was partially restored by progestin replacement. Although VEGF mRNA levels were unchanged, VEGF levels in follicular fluid increased 6-fold between 0-12 hrs post-hCG and remained elevated at 36 hrs. VEGF levels were not altered by steroid ablation. Second, the corpus luteum was collected in the early, mid, mid-late, and late luteal phase of the cycle. Whereas no significant changes in VEGF or ANG-2 mRNAs were observed, ANG-1 mRNA increased from early-to-mid luteal phase and then remained elevated through late in the cycle. Although VEGF mRNA levels were unchanged, immunocytochemical staining to VEGF protein in luteal cells was intense from early-to-mid luteal phase but slight by late luteal phase. Thus, there is transcriptional and translational control of ANG-1 and VEGF, respectively, in the ovulatory follicle and in the corpus luteum during the menstrual cycle. Endothelial-specific growth factors may be critical for ovulation of the follicle and for the development and maintenance of the microvasculature in the corpus luteum in primates. FUNDING NIH HD22408, HD18185 PUBLICATIONS Hazzard TM, Molskness TA, Chaffin CL, Stouffer RL. Changes in expression of VEGF and angiopoietin-1 in the periovulatory follicle of the rhesus macaque. In International Symposium on Ovulation Evolving and Clinical Concepts (held in Salt Lake City, UT, September 24-27, 1998), p 4 (abstract #4).
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