Marked changes in the circulating levels and ratios of angiopoietins during pregnancy, compared to natural menstrual cycles and controlled ovarian stimulation

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Evidence suggests that the angiogenic agent, angiopoietin-1 (ANGPT-1) and the angiolytic agent, angiopoietin-2 (ANGPT-2) have a role in blood vessel regulation in the ovary. This study was designed to determine if ANGPT-1 and −2 are detectable in the circulation of women and nonhuman primates, and whether their levels fluctuate in association with ovarian activity during reproduction. Venous blood samples were collected from rhesus monkeys during: (a) the natural menstrual cycle (n = 10), (b) controlled ovarian stimulation (COS) (n = 6), (c) the periovulatory interval in a 36-hr controlled ovulation [COv] protocol (n = 6), (d) following removal of the corpus luteum (CLX) or ovaries (OVX) (n = 5) and (e) during pregnancy (n = 8). Venous blood samples and follicular fluid were also obtained from women undergoing COS protocols during fertility treatment (n = 16). Total ANGPT-1 and −2 levels in serum were assayed using commercial immunoassays (Quantikine; R&D). Mean daily levels of ANGPT-1 and −2 were invariant in monkeys during the menstrual cycle with levels at menses of 48 ± 6 and 9 ± 1 ng/ml (x ± S.E.), respectively, resulting in an ANGPT-1:-2 ratio of 5.2. Mean levels did not vary during COv or COS, with ANGPT-1:-2 ratios of 4.5 and 1.3, respectively. There was no significant variation in ANGPT-1 or −2 levels following CLX or OVX. In contrast, ANGPT-2 increased (P<0.001) from luteal phase levels to 29 ± 10 ng/ml by 8–10 weeks of gestation, continued to rise (P<0.001) until 15–19 weeks (155 ± 42 ng/ml) and remained at this level in late gestation. ANGPT-1 levels did not increase, resulting in a reversal of the ANGPT-1:-2 ratio to 0.02 at 20–22 weeks of gestation. The ANGPT-1:-2 ratio was 20 at the time of egg retrieval in women during COS cycles. ANGPT-1 concentrations in follicular fluid were less than for ANGPT-2 (1 ± 0.2 ng/ml vs. 18 ± 4 ng/ml), resulting in a ratio of 0.06. ANGPT-1 and −2 are detectable in the blood stream of primates and women. ANGPT-1 is the predominant factor, but its levels are not influenced by ovarian events. The ANGPT-1:-2 ratio remained >1 during COv, COS and following CLX /OVX. Thus, the ANGPTs produced by the ovary (as evidenced by increased ANGPT-2 levels and altered ANGPT-1:-2 ratios in follicular fluid) are not major contributors to ANGPT in the circulation. The elevated circulating levels of ANGPT-2 during gestation may be of fetal-placental origin.