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1 Department of Animal Science, Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY, USA
2 Division of Animal and Veterinary Sciences, West Virginia University, Morgantown, WV, USADepartments of
3 Obstetrics and Gynecology–Perinatal Research Laboratories
4 Animal Sciences
5 Pediatrics, University of Wisconsin-Madison, Madison, WI 53715, USA
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(Received 29 December 2004;
accepted after revision 9 March 2005;
first published online 17 March 2005)
Corresponding author R. R. Magness: Department of Obstetrics and Gynecology, University of Wisconsin, Perinatal Research Laboratories, Atrium-B Meriter Hospital, 202 S. Park S., Madison, WI, 53715, USA. Email: rmagness{at}wisc.edu
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Introduction |
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Vascular endothelial growth factor (VEGF) is distributed widely throughout adult and fetal tissues (Shifren et al. 1994; Ahmed et al. 1995; Cheung, 1997; Tsoi et al. 2002; Chung et al. 2004). While there are numerous angiogenic factors that are associated with fetal development, VEGF appears to be one of the most potent factors associated with fetal and placental vascular growth in many species (Cullinan-Bove & Koos, 1993; Ahmed et al. 1995; Clark et al. 1996; Cheung, 1997; Winther et al. 1999; Charnock-Jones et al. 2001; Vonnahme et al. 2001; Vonnahme & Ford, 2004a, 2004b; Chung et al. 2004) including the sheep (Cheung, 1997; Cheung & Brace, 1999; Borowicz et al. 2002; Tsoi et al. 2002). Circulating concentrations of VEGF in fetal pigs, as well as placental VEGF mRNA expression, are positively associated with increased placental efficiency calculated as fetal weight divided by placental weight (Vonnahme & Ford, 2004a, 2004b). McKeeman et al. (2004) have demonstrated that circulating VEGF concentrations are increased as pregnancy progresses (i.e. 12, 20, 30 and 37 weeks) in the human. Furthermore, circulating concentrations of VEGF are correlated with placental volume and weight in the human (Wheeler et al. 1999), and therefore one might expect greater circulating concentrations of VEGF in dams carrying multiple fetuses compared to those carrying singletons.
In addition to its role in stimulating angiogenesis, VEGF has been shown to upregulate nitric oxide (NO) production by endothelial cells (Ahmed et al. 1997; Asahara et al. 1997; van der Zee et al. 1997; Parenti et al. 1998). In addition, Ni et al. (1997) showed developmental rises in uterine and placental tissue VEGF during pregnancy in the rat, and that VEGF was a potent in vitro vasodilator of uterine arteries via an endothelial-derived NO-mediated mechanism. Ku et al. (1993) also observed VEGF relaxation of coronary arteries is due to endothelial-derived NO. Uterine and/or placental NO synthase (NOS)-specific activity is increased early in pregnancy in the human (Williams et al. 1997) and sheep (Kwon et al. 2004b), and in association with rises in eNOS expression (protein and/or mRNA) uterine artery-specific activity has been shown to be elevated in late pregnant rats (Conrad et al. 1993), sheep (Nobunaga et al. 1996; Magness et al. 1996, 1997, 2001; Johnson et al. 1997) and humans (Brown et al. 1995; Sladek et al. 1997; Nelson et al. 2000). Recently we have reported that (Yi et al. 2005), utilizing freshly isolated uterine artery endothelial cells, both basal and stimulated (ATP or ionomycin) NO synthesis were greatest in pregnancy, less during the follicular phase and least during the luteal phase.
As angiogenesis and vasodilatation in the uterine and placental vascular beds are important at all stages of pregnancy (i.e. early, middle and late), it is necessary to characterize how VEGF and NO change in the circulation throughout gestation. In the current study, early placentation in the ewe was defined as the first 50 days of pregnancy (early) with maximal placental growth occurring up to 
day 90 (middle) and the period of maximal fetal growth occurring from day 100 to term (late). Therefore the objectives of the current study were to evaluate the systemic levels of VEGF and NO metabolite (NOx) throughout ovine gestation and to determine if there was an effect of sheep carrying singleton versus multiple fetuses. We hypothesized that ewes with multiple fetuses and their correspondingly greater placental mass would have higher levels of both NO and VEGF throughout gestation, and that the pattern of change in the two would be temporally associated.
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Both the University of Wisconsin-Madison Research Animal Care and Use Committee and the West Virginia University Animal Care and Use Committee approved the procedures for sample collections. Ewes were synchronized for breeding as previously described (Magness et al. 1991, 2001; Johnson et al. 1997; Gibson et al. 2004) or induced to breed out of season with an injection (I.M.) of 25 mg of progesterone at ram introduction followed by an injection (I.M.) of 20 mg of prostaglandin F2
(Lutalyse, Pharmacia Animal Health, Kalamazoo, MI, USA) 14 days later. Starting on day 27 of gestation, whole blood was obtained by jugular venepuncture from 50 pregnant sheep at the University of Wisconsin, and 150 pregnant sheep at West Virginia University. Initial pregnancy diagnosis and counts of embryos were done with ultrasonography using an Aloka 500 (Corometrics Medical Systems, Wallingford, CT, USA) with a 7.5 mHz linear transrectal probe from days 25–30. An Oviscan 4 (BCF Technology, Ltd. Livington, Scotland, UK) with a 3.5 mHz transabdominal sector probe was used to recheck pregnancy and recount fetuses on days 45–50 and 65–70. Thereafter, fetal number was determined by the number of lambs born. Ewes were bled intermittently during the breeding season and one week into the postpartum period. Further, samples were obtained in seven non-pregnant ewes. Blood was centrifuged to remove the whole blood elements and the samples were stored at –20°C until assayed for NOx and VEGF.
NO analysis
A 500 µl blood sample was added to 1 ml chilled 100% ethanol, vortexed and centrifuged. The supernatant was used to measure NOx using a Seivers instrument model 280 NO analyser (Boulder, CO, USA), which measures NOx based on gas-phase chemiluminescence reaction between NO and ozone. Briefly, samples were injected in the purge vessel where nitrates and nitrites in the sample react with V3Cl3 to produce NO. The NO gas then flowed into the NO analyser where it reacted with ozone to produce nitrite, which could be quantified by luminescence. The area under the peak was calculated and the amount of NO in the sample was compared to the standard curve (Bird et al. 2000; Zheng et al. 2000; Magness et al. 2001; Rupnow et al. 2001).
VEGF radioimmunoassay
A radioimmunoassay (RIA) for VEGF was performed as previously described (Vonnahme et al. 2003). Briefly, human, recombinant VEGF165 (cold hormone; G143AB; Genentech, Inc., Los Angeles, CA, USA), primary antibody (polyclonal rabbit antiserum to VEGF165; no. 27906-17, Genentech, Inc., Los Angeles, CA, USA) and human, recombinant [125I]-VEGF165 (tracer; NEX328, NEN Life Science Products, Inc, Boston, MA, USA) were used. Sensitivity averaged 25 pg ml–1, defined as the VEGF standard yielding 95% of the counts in the buffer control tube. Within-assay variability for VEGF was determined by assaying a pool of systemic plasma from a pregnant ewe to which known quantities of VEGF had been added (0.0, 0.5 and 5.0 ng ml–1 plasma). The resulting concentrations (±S.E.M.), after subtraction of the plasma blank (1.46 ± 0.11 ng ml–1) averaged 0.62 ± 0.04 ng ml–1 (n= 4) and 5.42 ± 0.16 ng ml–1 (n= 4), respectively. Coefficients of variation averaged 10.7%, 8.2% and 5.8% for the plasma blank, 0.5 and 5.0 ng ml–1 VEGF additions, respectively. Parallelism was obtained between a doubly diluted pregnant plasma pool and the standard curve. No cross-reactivity was found with basic fibroblast growth factor or 2-macroglobulin (Sigma, St Louis, MO, USA) at concentrations as high as 100 mg l–1.
Statistical analysis
Gestational days were compared in the following groups: days (d) 20–39 (n= 173), d 40–59 (n= 173), d 60–69 (n= 173), d 70–79 (n= 7), d 80–89 (n= 10), d 90–99 (n= 14), d 100–109 (n= 19), d 110–119 (n= 40), d 120–129 (n= 48), d 130–139 (n= 35), d 140 to term (n= 12), non-pregnant (n= 7) and postpartum ewes (n= 14). Table 1 shows the n values and average gestational ages separated according to whether they were singleton or multiple pregnancies. Data were analysed by using PROC GLM (general linear model) procedures of SAS with main effects being gestation and number of fetuses present. LSMEANS (least square means) procedure was used for means separation. Further correlations within a group between NO and VEGF were compared using PROC CORR (correlations) procedures of SAS. Data presented are means ± standard error of the mean (S.E.M.).
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Discussion |
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In order to maintain normal oxygen and nutrient delivery for proper fetal growth and development, uteroplacental blood flows increase 30- to 50-fold during pregnancy (Rosenfeld, 1984; Reynolds & Redmer, 1995; Magness & Zheng, 1996; Sladek et al. 1997; Magness, 1998; Magness et al. 2001). Moreover, to support this dramatic increase in volumetric flow, the uterine vascular bed must both vasodilate and proliferate. In this study, we demonstrate a biphasic pattern of circulating NOx concentrations, with the initial peak occurring around days 40–69 of gestation, and a linear increase from day 100 to term. NOx levels during pregnancy are substantially increased over those in non-pregnant sheep as early as days 20–39 of gestation. Likewise, Kwon et al. (2004b) demonstrated that the ovine placentome (as well as the intercotyledonary placental membranes and intercaruncular endometrium) produces NO in a similar biphasic pattern. They reported increases in 3H-arginine to 14C-citrulline conversion (NO synthesis-specific activity) being observed from days 30–60 of gestation, declining on day 80 and increasing again on day 100. Because the intercotyledonary placenta and intercaruncular endometrium NO synthesis were only 25% of placentome production, the pattern of NOx that we detect in circulating maternal plasma is probably due in part to the rises in both NOS activity and the total eNOS capacity/mass detected in the placentome. We have also evaluated the fetal compartment and noted amniotic fluid rises in NOx and the biological second messenger for NO, cGMP, in association with rises in placental artery endothelial eNOS protein expression during the fetal growth period (Sheppard et al. 1997; Zheng et al. 2000). We cannot be specifically certain if NOx is of maternal or fetal origin in the current study. However, it is known that eNOS-specific activity and/or eNOS expression (total synthesis capacity) is greater in uterine artery endothelium from pregnant compared to non-pregnant guinea pigs (Weiner et al. 1994), sheep (Magness et al. 1996, 1997, 2001), and humans (Nelson et al. 2000). Recently we substantiated these conclusions by performing direct imaging of real-time intracellular NO production by uterine artery endothelium acutely isolated from pregnant and non-pregnant sheep and found a substantial elevation of NO due to pregnancy status (Yi et al. 2005).
While NO is a small, diffusible molecule and thus easily transported from the fetal to maternal circulation, VEGF is a large glycoprotein (45 kDa), which is unlikely to be able to move from the fetal to the maternal compartment. Therefore the VEGF levels we observed in the maternal systemic circulation are probably derived from maternal rather than fetal tissues in the sheep. A decline in VEGF concentrations early in pregnancy was surprising considering the studies in the human (Wheeler et al. 1999), where VEGF is elevated in pregnant versus non-pregnant blood samples. While VEGF concentrations in the human increase in pregnancy, so do the circulating levels of soluble Flt-1 (sFlt-1), a plasma protein that binds VEGF and prevents it from binding to target cells (Molskness et al. 2004). In samples obtained from the pig (Vonnahme & Ford, 2004a, 2004b) and sheep (current study), we could not detect any factor that would bind up VEGF, indirectly suggesting a lack of sFlt-1 in ovine blood samples. Due to the inherent differences in placental types (i.e. modified epitheliochorial in the sheep and haemochorial in the human), sFlt-1 may be important in human circulation to control VEGF in the maternal system. On the other hand, in domestic farm animals, VEGF cannot get out into the maternal circulation due to the increased number of cellular layers between the maternal and fetal blood streams, obviating the need for increased maternal sFlt-1. The fall in VEGF concentrations that we observed early in ovine pregnancy were temporally associated with, and therefore are likely to be responsible for, additional, as yet unidentified, physiological events that occur up to day 70 in the sheep. More specifically, Stegeman, 1974) demonstrated an initial decline in uterine vascular density days 40–55 before rebounding by day 70. Furthermore, mRNA analysed by real-time RT-PCR in ovine caruncular tissue shows a 90% reduction from day 12 of pregnancy to day 40 of pregnancy (PP Borowicz and LP Reynolds, NDSU, ND, USA, personal communication). From day 70 to term, VEGF mRNA in caruncular tissue does not increase (Borowicz et al. 2002). In numerous reproductive tissues oestrogen regulates the levels of VEGF expression (Reynolds & Redmer, 1995, Reynolds & Redmer, 2001), including uterine vascular endothelium (Cullinan-Bove & Koos, 1993; Magness et al. 2004; Zaitseva et al. 2004). Moreover, Carnegie & Robertson (1978) demonstrated that oestradiol and placental fluid concentrations are actually decreasing from day 50 to day 70 of gestation in the sheep. Therefore, the decrease in circulating VEGF concentrations from day 20 to day 70 may be explained by the reduction in oestradiol concentrations, and VEGF mRNA expression in the caruncle (PP Borowicz and LP Reynolds, personal communication). The decrease in maternal vascular density during this time may be a result of the decline in VEGF production. Millaway et al. (1989) further demonstrated a decrease in angiogenic activity of day 22 caruncular tissues compared to day 17 pregnant caruncular tissues. While cotyledonary angiogenic activity increased throughout gestation in the ewe, caruncular tissue angiogenic activity decreased from day 40 to day 65 of gestation, and remained relatively constant until term. These data further indicate that the surprising early transient decrease followed by a return to non-pregnant VEGF concentrations in maternal circulation may be due to a reduction in maternal production of VEGF.
As early as day 11 of ovine gestation, blood flow to the gravid uterine horn increased (Greiss & Anderson, 1970; Reynolds et al. 1984), primarily due to vasodilatation. By day 24, increases in microvascular volume are present in the caruncular (maternal) portion of the placenta (Reynolds & Redmer, 2001). There continue to be increases in capillary proliferation of the fetal vasculature as well as vasodilatation of the maternal vascular network (Stegemen, 1974). Therefore, throughout gestation, there are continuous modifications of the vascular networks associated with the fetal and maternal tissues. In the current study, we divided gestation into three periods (akin to trimesters in the human), i.e. ‘early’ placentation, days 20–59; the ‘middle’ period of exponential placental growth, days 60–99; and the ‘late’ exponential fetal growth, day 100–term. We only observed an overall increase in both circulating VEGF and NO during the period of exponential fetal growth, although the former was quite minor at best. A significant increase in uteroplacental mass of the pregnant sheep occurs during mid-gestation, when placental weight is the heaviest (day 90; Stegeman, 1974; Rosenfeld, 1984; Reynolds & Redmer, 2001). Thereafter, the ‘late’ fetal period of gestation is the period of greatest absolute total increase in uterine perfusion. In the present study, within each period, there was more NOx in circulation associated with increased numbers of fetuses (Fig. 3). Recent studies have shown that local uterine arterial inhibition of NOS activity using L-NAME given to late pregnant sheep decreases uterine venous NO second messenger cGMP levels (Rosenfeld et al. 1996) and uterine blood flow (Miller et al. 1999). Therefore the vasodilatation during the third trimester is partly mediated through this rise in NO production. On day 105 of gestation, ewes carrying triplets have 50% higher uterine blood flow values compared to ewes carrying either singles or twins, in association with increased nutrient delivery to the gravid uterus (Christenson & Prior, 1978). The increase in uterine blood flow to sustain a triplet pregnancy may indeed be driven by NO. Previously, it was determined that ewes carrying multiple fetuses have increased NOx levels in circulation from 110 to 130 days of gestation. In this study, we confirm these observations that NOx is increased during the later part of gestation with ewes carrying triplets, but show that the secondary more robust rise in NOx begins earlier in ewes carrying multiples versus singletons (90–99 days versus 100–109 days, respectively). Increased NOx in ewes carrying multiple fetuses compared to singletons during mid-pregnancy could potentially aid in the remodelling of the vascular bed prior to the increased demand for blood flow during the third trimester of pregnancy in ewes carrying multiple fetuses.
The fetal period of gestation is associated with dynamic elevations in uteroplacental blood flow necessary for the substantial increase in metabolic demands of fetal growth (Ford, 1982; Rosenfeld, 1984; Magness et al. 1996; Sladek et al. 1997; Magness, 1998). Maternal diet has a huge impact on the ability of nutrients to be delivered to the fetus as protein-restricted rat dams have an attenuated uterine artery vasodilatory response to VEGF, because of a reduction in the NO component of the VEGF-mediated vasorelaxation (Ni et al. 1997; Itoh et al. 2002). This indicates that maternal nutrition as well as the numbers of fetuses influence uteroplacental vasodilatation. Maternal undernutrition in sheep (50% USA-Nutrition Research Council recommendations) from day 28–78 of gestation results in a 32% reduction in fetal weight (Vonnahme et al. 2003) and decreases the metabolic precursor for NO, L-arginine levels in fetal plasma and allantoic fluid (Kwon et al. 2004a). Recent epidemiological studies indicate that intrauterine growth restriction may be a predictor of adult onset diseases (i.e. obesity, type II diabetes, hypertension, coronary heart disease). If indeed placental size and nutrient extraction efficiency are related to circulating concentrations of VEGF and NOx, then during human pregnancy, being able to measure these hormones may be indicative of conceptus health and have important implications for fetal size, birth weight and fetal/developmental origins of adult disease. The results of this study suggest that the sheep is not a useful model for detecting VEGF in the maternal circulation, due to species differences in placental type, but that circulating NO may still be a useful indicator of fetal health. Ideally, an indication of fetal wellbeing found by monitoring circulating maternal factor(s) would aid in early treatment of potential health risks to the fetus and/or the mother.
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Author's present address
K. A. Vonnahme: Department of Animal and Range Sciences, North Dakota State University, PO Box 5727, Fargo, ND 58105, USA
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