High maternal serum alpha-fetoprotein (AFP) levels during pregnancy may be instrumental in reducing the subsequent risk of breast cancer. This hypothesis was tested in a nested case-control study using stored frozen sera accrued between 1959 and 1966 by the University of California at Berkeley Child Health and Development Studies (CHDS) group from a cohort of pregnant women. Cases with histologically confirmed breast cancer were identified from California Cancer Registry files covering their date of enrollment in the CHDS until 1994. Controls were selected from the CHDS cohort by using randomized recruitment. Third-trimester maternal serum AFP levels were analyzed by using both a radioimmunoassay and an immunoenzymatic method. After controlling for multiple confounders in logistic regression models, the authors found an inverse association between high levels of maternal serum AFP (top quartile) during the index pregnancy and the risk of breast cancer. The protective effect of high levels of maternal serum AFP varied by age at first full-term pregnancy (age 20 years or less: odds ratio (OR) = 0.43, 95% confidence interval (CI) 0.28-0.65; age 21-23 years: OR = 0.62, 95% CI 0.41-0.92). After age 27 years, the estimated risk exceeded unity (OR = 1.67, 95% CI 1.14-2.45). These study findings suggest that some of the protection against breast cancer conferred by early first full-term pregnancy may result from high levels of maternal serum AFP. After age 27 years, a high maternal serum AFP level is not protective and may increase risk.
Episodic reductions in uteroplacental blood flow play a crucial role in the altered vascular reactivity seen in Occluder animals and may represent a new model to investigate the mechanisms associated with episodic reductions in uteroplacental blood flow in pathological pregnancies.
The etiology of preeclampsia remains unknown. However, a contributing factor to this hypertensive disease of pregnancy is a reduction in uterine perfusion pressure resulting in placental ischemia. Uterine arteries may be a major regulator of this process through changes in vascular reactivity and localized blood flow. The reduced uterine perfusion pressure (RUPP) pregnant rat is an established animal model of preeclampsia pathology. Pregnant Sprague Dawley rats were used for this investigation and subjected to RUPP or SHAM surgery on Day 14 of gestation. On Day 21 of gestation, animals were terminated and resistance-caliber uterine arteries were harvested and mounted on a pressurized arteriograph to examine myogenic reactivity, agonist induced vasodilation (methacholine and VEGF), and vasoconstriction (phenylephrine and U-46619). Resistance-caliber uterine arteries from RUPP animals exhibited increased myogenic reactivity and decreased vasodilation (methacholine and VEGF) compared to SHAM uterine arteries (p<0.05). Phenylephrine and U-46619 induced constriction was similar in uterine arteries between RUPP and SHAM rats. These results suggest that resistancecaliber uterine arteries from RUPP pregnant rats are altered to reflect a more constrictive phenotype which may play a role in the development of maternal hypertension demonstrated in these animals and thereby potentially in preeclampsia.
Preeclampsia is a multifaceted disease of pregnancy mediated by poor placental perfusion. The symptoms of the disease include hypertension, hyperuricemia, and proteinuria. Pregnant rats with reduced uteroplacental perfusion (RUPP) have been used as an animal model of preeclampsia. In these animals plasma ascorbate levels are decreased along with increased vascular reactivity similar to what is seen in patients with preeclampsia. Therefore, the aim of this study was to determine the effects of dietary ascorbic acid (AA) treatment to animals with RUPP and to see if detrimental changes in mesenteric vascular reactivity seen in RUPP rats can be ameliorated. Sprague Dawley rats were subjected to RUPP or Sham surgery on Day 14 of gestation. Animals were then given regular water or ascorbic acid water (1 mg/mL) ad libitum post surgery. At gestational Day 21, resistance‐sized mesenteric arteries were harvested and mounted in a pressurized arteriograph. Myogenic reactivity was significantly decreased in AA treated RUPP animals compared to RUPP (p<0.05). AA also reversed RUPP induced decreases in methacholine relaxation seen in RUPP (p<0.05). These results suggest that antioxidant treatment can partially reverse the increased myogenic reactivity and decreased endothelium‐dependent relaxation seen in animals with reductions in uterine perfusion and may provide new insights into the treatment of human preeclampsia.
We have recently demonstrated that periodic reductions in uterine perfusion pressure in pregnant rats results in maternal hypertension and a constrictive phenotype of resistance‐sized mesenteric arteries. The purpose of this study was to examine the effects of periodic reductions in uterine perfusion pressure on uterine artery myogenic reactivity and vasodilation. An aortic occluder was implanted on Day 14 of gestation. The occluder allows uterine perfusion pressure to be reduced by 40% for 1hr a day for 5 consecutive days. Animals were terminated on gestational Day 21 and resistance‐sized uterine arteries were mounted on a pressurized arteriograph where myogenic reactivity and agonist (methacholine) vasodilation were assessed and compared to responses of arteries from SHAM‐operated controls. Myogenic reactivity was increased in resistance‐sized uterine arteries from Occluder animals compared to SHAM (p<0.05). Methacholine dilation of resistance‐sized uterine arteries was reduced in Occluder rats compared to SHAM (p<0.05). These data suggest that Occluder animal uterine artery vasoreactivity is altered toward a more contractile phenotype than SHAM and may play a role in the pathology associated with the model. We speculate that similar changes may have relevance in the pathology of preeclampsia.
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