Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

Abstract

Abstract-The renin-angiotensin system (RAS) participates in preeclampsia; however, the relative contributions from the circulating RAS and the tissue-based, uteroplacental RAS are unknown. We hypothesized that the tissue-based uteroplacental RAS is dysregulated in preeclampsia. We performed microarray and gene expression studies and confirmed the findings on the protein level by immunohistochemistry in ureteroplacental units from 10 preeclamptic women and 10 women with uneventful pregnancies. All of the women were delivered by cesarean section. We also analyzed plasma renin activity and circulating agonistic angiotensin II type 1 (AT 1 ) receptor autoantibodies. In preeclampsia, we found that the angiotensin II AT 1 receptor gene was 5-fold upregulated in decidua (maternal origin). We also found AT 1 autoantibodies in preeclamptic women and in their offspring by neonatal cardiomyocyte bioassay compared with women with normal pregnancies and their infants (mother: 17.5Ϯ2.2 versus 0.05Ϯ0.4; fetus: 14.5Ϯ1.8 versus 0.5Ϯ0.5 ⌬bpm). Gene expressions for renin (35.0-fold), angiotensin-converting enzyme (2.9-fold), and angiotensinogen (8.9-fold) were higher in decidua than placenta (fetal origin) in both control and preeclamptic women, whereas the AT 1 receptor was expressed 10-fold higher in placenta than in decidua in both groups. Our findings elucidate the ureteroplacental unit RAS in preeclamptic and normal pregnancies. We found that, in preeclampsia, the AT 1 receptor expression is particularly high in decidua, combined with pregnancy-specific tissue RAS involving decidual angiotensin II production and AT 1 autoantibodies. We also showed that AT 1 autoantibodies cross the ureteroplacental barrier. These components could participate in the pathophysiology of preeclampsia.

Regulation of renin-angiotensin system in gestational hypertension

“…The interplay between ACE and ACE2 may govern the formation and metabolism of Ang effector peptides. No statistical difference was seen in the levels of ACE and ACE2 between normal and gestational hypertension, which is consistent with most previous studies [8,22,27], except the study of Ito et al, which reported significant increases in ACE mRNA and protein in the preeclamptic placenta. Reasons behind the difference are unclear.…”

“…Ang (1-7) is considered to have a counteracting effect to Ang II on the cardiovascular system by its inhibition of cell migration and proliferation [5,21,28]. Expression of AGT was found in our study, and no significant difference was found in the placenta of normal versus gestational hypertension, which was consistent with the study of Herse et al [8]. However, in the study of Lauren et al, AGT mRNA was higher in the chorionic villi obtained from preeclamptic subjects [22].…”

“…Shah et al [7] demonstrated an increase in renin level in the deciduas vera of preeclamptic women. On the contrary, Herse et al [8] argued that without any increase of other local RAS components observed in decidua of preeclamptic patients except angiotensin receptors AT1R. Anton et al [9] reports in a clinical trial that AT1R mRNA and Ang II level was significantly higher in preeclampsia patients compared with normal pregnancies, despite a decrease in circulating Ang II.…”

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

“…A recent study by Herse et al showed that AT1 receptor mRNA expression was 10-fold higher in the placenta than in the decidua tissues in both normal and preeclamptic pregnancies, but no difference was noticed for AT1 mRNA expression between normal and preeclamptic placental tissues [34]. In addition, AT1 autoantibody was also found in fetal serum in AT1 autoantibody positive mother complicated with preeclampsia [34]. However, whether AT1 autoantibody exerts any effects on AT2 receptor in VSMCs is not known.…”

“…AT1 plays important roles in angiogenic, inflammatory and oxidative stress responses in the placental vasculature [30][31][32][33]. A recent study by Herse et al showed that AT1 receptor mRNA expression was 10-fold higher in the placenta than in the decidua tissues in both normal and preeclamptic pregnancies, but no difference was noticed for AT1 mRNA expression between normal and preeclamptic placental tissues [34]. In addition, AT1 autoantibody was also found in fetal serum in AT1 autoantibody positive mother complicated with preeclampsia [34].…”