Systemic and uteroplacental renin--angiotensin system in normal and pre-eclamptic pregnancies

Abstract

Pregnancy is characterized by an increase in many of the different components of the circulating renin-angiotensin system (RAS). However, the physiological mechanisms of stimulated RAS activity during pregnancy are unknown. Even less understood is how this system may be altered in pre-eclampsia, a hypertensive disorder of pregnancy. Additional studies have shown the presence of a local tissue specific RAS in the uteroplacental unit of normal and pre-eclamptic pregnancies. Differences in normal pregnant and pre-eclamptic RAS component regulation may provide insight into the mechanisms responsible for the clinical pathological features of pre-eclampsia. Specifically, this review summarizes the key findings in the circulating and uteroplacental RAS in normal and pre-eclamptic pregnancies.

Fig. 1

Localization of Ang-[1-7) and ACE2 in the placenta. The diagram shows a cross-section of the human placenta illustrating the sections of the placenta and decidua that were stained for Ang-[1-7] and ACE2 by immunohistochemistry. In this diagram, different tissue types of the placenta are identified by letters which correspond to the matching immunostained pictures; immunohistochemical expression of Ang-[1-7] [left] and ACE2 [right] can been seen in the decidua [A and B], syncytiotrophoblasts and cytotrophoblasts [C and D], and the vascular smooth muscle and endothelium of the fetal vessels [E and F]. Positive staining is brown and nuclear counterstaining is blue. Quantification of the intensity of expression of Ang-[1-7] and ACE2 in syncytiotrophoblasts revealed no differences between normal and pre-eclamptic pregnancies; however, there was a significant increase in Ang-[1-7] immunostaining in pathological first trimester pregnancies [Valdes et al. 2006].

Fig. 1

Localization of Ang-[1-7) and ACE2 in the placenta. The diagram shows a cross-section of the human placenta illustrating the sections of the placenta and decidua that were stained for Ang-[1-7] and ACE2 by immunohistochemistry. In this diagram, different tissue types of the placenta are identified by letters which correspond to the matching immunostained pictures; immunohistochemical expression of Ang-[1-7] [left] and ACE2 [right] can been seen in the decidua [A and B], syncytiotrophoblasts and cytotrophoblasts [C and D], and the vascular smooth muscle and endothelium of the fetal vessels [E and F]. Positive staining is brown and nuclear counterstaining is blue. Quantification of the intensity of expression of Ang-[1-7] and ACE2 in syncytiotrophoblasts revealed no differences between normal and pre-eclamptic pregnancies; however, there was a significant increase in Ang-[1-7] immunostaining in pathological first trimester pregnancies [Valdes et al. 2006].

Fig. 2

Angiotensin peptide expression in the chorionic villi of normal and pre-eclamptic pregnancies. Measurement of the RAS peptides Ang I [A], Ang II [B], and Ang-[1-7] [C] by radioimmunoassay revealed an increase in Ang II expression in pre-eclamptic chorionic villi when compared with normal pregnancies. No changes were seen in Ang I or Ang-[1-7] peptide levels. In addition, Ang II was found to be the predominant peptide in the chorionic villi of both normal and pre-eclamptic pregnancies [Anton et al. 2008. ^*p<0.05m normal.

Fig. 3

Relative gene expression of angiotensinogen, renin, AT₁ receptor, and Mas receptor in the chorionic villi of normal and pre-eclamptic pregnancies. Angiotensinogen [A], renin [B], AT₁ receptor [C], and Mas receptor [D] mRNAs were measured by real time RT-PCR. Angiotensinogen and AT₁ receptor mRNA were increased in the chorionic villi of pre-eclamptic pregnancies vs those from normal pregnancies. In addition, there was a modest decrease in Mas receptor mRNA in the pre-eclamptic chorionic villi. No significant changes were seen in renin mRNA expression, although a trend was observed for an increase in renin in pre-eclamptic chorionic villi [Anton et al. 2008]. *p<0.05 m normal.

Fig. 4

Receptor binding of angiotensin receptor subtypes in the chorionic villi of normal and pre-eclamptic pregnancies. Receptor binding of RAS receptor subtypes. AT_1, AT_2, and AT_1-7, was measured by receptor autoradiography utilizing radiolabeled ¹²⁵I-Sarthran. Photomicrographs show the distribution of ¹²⁵I-Sarthran binding from normal pregnant and preclamptic chorinic villi. The photomicrographs show, respectively, total binding, non-specific binding in the presence of the competitor Sarthran, the results of competition by the AT₁ receptor antagonist losartan [3 μM], the AT₂ receptor antagonist PD123319 [3 μM], and the AT_1-7 receptor antagonist A779 [3 μM]. Intensity of the staining is represented by a color spectrum where red indicates intense receptor binding and blue indicates very low receptor binding. (see Table 1] Quantification of the receptor density showed that the AT₁ receptor is the predominant RAS receptor in chorionic villi of both normal and pre-eclamptic pregnancies. The receptor density of the AT₂ and AT_1-7 receptors were low and made up less than 15% of the total RAS receptor binding in the chorionic villi. No changes in receptor density in the chorionic villi of normal versus pre-eclamptic pregnancies were seen in any of the three angiotensin receptor subtypes [Anton et al. 2008].

Fig. 5

Contrasting changes in the Ang II levels found in the circulation and chorionic villi of normal and pre-eclamptic pregnancy. Expression of Ang II is significantly decreased in the circulation of pre-eclamptic women. However, the expression of local tissue Ang II is increased in the chorionic villi of the preclamptic placenta. This data provider evidence for differential regulation of Ang II in the circulation versus in the placental chorionic villi in pre-eclamptic women.