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Departments of Obstetrics and Gynecology, Perinatal Research Laboratories (I.M.B., J.Z., J.M.C., R.R.M.), and Meat and Animal Science (R.R.M.), University of Wisconsin - Madison, Madison, Wisconsin 53715
Address all correspondence and requests for reprints to: Ian M. Bird, Ph.D., University Wisconsin - Madison, Department Obstetrics and Gynecology, Perinatal Research Laboratories, 7E Meriter Hospital/ Park, 202 South Park St., Madison, Wisconsin 53715. E-mail: IMBird{at}FACSTAFF.Wisc.edu
During pregnancy, the uterine artery demonstrates refractoriness to vasoconstriction by infused angiotensin II (AII). AII increases prostacyclin (PGI2) production by uterine artery endothelium from pregnant ewes, and this response is mediated via the AT1 receptor (AT1-R). This response is also unique to pregnancy because AII does not stimulate PGI2 production by uterine artery endothelium from nonpregnant ewes. We therefore hypothesize that the increase in uterine artery PGI2 production in response to AII in pregnancy is associated in part with a concomitant increase in AT1-R expression in uterine artery endothelium. Endothelium-derived protein was directly removed from the lumenal surface of freshly isolated uterine and systemic (omental) arteries from nonpregnant and pregnant ewes. AT1-R expression was then measured in both the endothelium-derived fraction and endothelium-denuded vascular smooth muscle (VSM) fraction by Western analysis. AT1-R was detected as 54- and 65-kDa proteins in all samples, as well as adrenal cortex control. AT1-R expression increased more than 8-fold in uterine artery endothelium of pregnant ewes over that in nonpregnant ewes at each of four gestational ages (P < 0.05 at 110, 120, 130, 142 days, n = 4 each vs. n = 6 nonpregnant). No significant differences were seen, however, from 110 to 142 days of gestation. In contrast, whereas the level of AT1-R staining in omental artery endothelium in nonpregnant ewes was higher than in uterine artery, AT1-R increased less in pregnant ewes (2-fold) and only reached significance over nonpregnant values at 110 and 120 days, or when data was combined irrespective of gestational age (P < 0.05). Although AT1-R was also detected in uterine and omental artery VSM, little or no change in expression was observed in pregnancy. Results were confirmed by immunohistochemical staining of arterial cross sections, and the increase in AT1-R expression in uterine artery endothelium was confirmed by RT/PCR amplification of AT1-R messenger RNA from collagenase dispersed cells (n = 4 pregnant vs. n = 4 nonpregnant, mean 20-fold increase, P < 0.028). We conclude that increased uterine artery endothelial PGI2 responsiveness to AII during pregnancy is indeed associated with a correspondingly marked and localized increase in expression of the endothelial AT1-R receptor. We believe our findings allow a more detailed understanding of the molecular mechanisms that underlie increased uterine blood flow that is so central to the normal development of the growing fetus, and on dysfunction may lead to conditions such as preeclampsia.
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