Longitudinal study of angiotensin peptides in normal and pre-eclamptic pregnancy

Abstract

Purpose: To address whether differential regulation of the renin-angiotensin-aldosterone system occurs in pre-eclampsia, we performed an analysis of the time course of circulating and urinary profiles of the vasoconstrictor (Ang II) and the vasodilator [Ang-(1-7)] peptides in normal pregnant (NP) and pre-eclamptic (PE) women.

Methods: Urine and plasma samples from 86 nulliparous women were collected prospectively; 67 subjects continued as NP and 19 developed PE. Subjects were enrolled prior to 12 weeks of gestation and plasma and spot urine samples were obtained throughout gestation. Control samples were obtained at 6 weeks postpartum (PP).

Results: Mean blood pressure (p < 0.001) was elevated at 31-37 weeks of gestation in PE subjects as compared with NP subjects. Plasma Ang I and Ang II levels were elevated in NP subjects as early as 16 weeks of gestation and maintained throughout gestation. In PE subjects both plasma Ang I and Ang II were elevated at 16-33 weeks as compared with PP levels. PE subjects showed reduced plasma Ang I and Ang II (at 35-37 weeks of gestation) compared with NP subjects. Plasma Ang-(1-7) was unchanged in both groups. All three urinary peptides increased throughout gestation in NP subjects. In PE subjects urinary Ang I was increased at 23-26 weeks and was maintained throughout gestation. Urinary Ang II was increased at 27-29 and 31-33 weeks of gestation. PE subjects had no change in urinary Ang-(1-7).

Conclusion: The activation of the RAS, particularly Ang II throughout normal gestation may contribute to the maintenance of vascular tone during normal pregnancy. However higher sensitivity to Ang II in pre-eclampsia may be potentiated by the higher circulating and urinary levels of Ang II, unopposed by local renal Ang-(1-7), and thus may contribute to the development of pre-eclampsia.

Keywords: Angiotensin peptides; Circulation; Pre-eclampsia; Urinary excretion.

Fig. 1

Systolic (SBP), Diastolic (DBP), and Mean (MBP) blood pressure in normal and pre-eclamptic pregnant subjects over gestation. The postpartum (PP) time point was used as the basis of control comparisons. Two-way ANOVA showed a significant effect of preeclampsia and weeks of gestation. For normal subjects N = 23, 63, 57, 59, 64, 63, 67 for <16, 16–20, 23–26, 27–29, 31–33, 5–37 weeks of gestation and PP, respectively. For pre-eclamptic subjects, N = 7, 19, 15, 18, 17, 16, 19 for <16, 16–20, 23–26, 27–29, 31–33, 35–37 weeks of gestation and PP, respectively. *p < 0.05, **p < 0.01 vs. PP ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 vs. normal pregnancy at the same week of gestation. Although not shown on the figure, there were significant differences in pre-eclamptic subjects for SBP and MBP between <16, 16–20, and 23–26 vs. 35–37 (p < 0.01) weeks of gestation; and for DBP between 16–20, and 23–26 vs. 35–37 weeks of gestation (p < 0.01)

Fig. 2

Plasma Ang I, Ang II, and Ang-(1–7) levels in normal and preeclamptic pregnant subjects over gestation and at PP. Two-way ANOVA showed the significant effects of gestation and pre-eclampsia. For normal subjects N = 22–62, for pre-eclamptic subjects N = 7–19. *p < 0.05, **p < 0.01, ***p < 0.001 vs. PP; ^#p < 0.05, ^###p < 0.001 vs. normal pregnancy at the same week of gestation. Although not shown on the figure, there were significant differences for plasma Ang I in normal subjects <16 vs. 31–33 and 36–37 weeks (p < 0.05); for plasma Ang I in pre-eclamptic subjects 16–20, 23–26, 27–29 vs. 35–37 weeks (p < 0.05); for plasma Ang II in pre-eclamptic subjects 27–29 vs. 35–37 weeks (p < 0.05)

Fig. 3

Urinary Ang I, Ang II, Ang-(1–7) levels in normal and preeclamptic pregnant subjects over gestation and at PP. Two-way ANOVA showed the significant effects of gestation and pre-eclampsia. For normal subjects, N = 14–53, for pre-eclamptic subjects N = 5–17. *p < 0.05, **p < 0.01, ***p < 0.001 vs. PP. Although not shown, there were significant differences for urinary Ang II levels in normal subjects between 16 and 20 vs. 27–29, 31–33, 35–37 weeks (p < 0.05); for urinary Ang-(1–7) in normal subject between <16 vs. 27–29, 31–33 weeks (p < 0.05) and between 16–20 vs. 27–29, 31–33, 35–37 weeks (p < 0.05)

Fig. 4

Relationship of mean blood pressure (MBP) vs. plasma (P) and urinary (U) Ang I, Ang II, and Ang-(1–7) during normal and pre-eclamptic pregnancy. No significant correlation was found for normal subjects and for MBP vs. U Ang II in pre-eclamptic subjects. The level of significance of the linear regression line for U Ang I and U Ang-(1–7) for the preeclamptic group is indicated in each graph. Values are mean ± SEM for both MBP and angiotensin peptide data

Fig. 5

Systolic, diastolic, and mean blood pressure in mild and severe pre-eclamptic pregnant subjects over gestation and at PP. Two-way ANOVA revealed a significant overall effect of mild vs. severe on DBP and weeks of gestation for DBP and MBP. For mild preeclamptic subjects, N = 6, 14, 10, 14, 14, 13, and 14; for <16, 16–20, 23–26, 27–29, 31–33, 35–37 weeks of gestation and PP, respectively. For severe pre-eclamptic subjects, N = 1, 5, 5, 4, 3, 3, 5 for <16, 16–20, 23–26, 27–29, 31–33, 35–37 weeks of gestation and at PP, respectively. *p < 0.05, **p < 0.01, ***p < 0.001 vs. PP. ^##p < 0.01, ^###p < 0.001 vs. mild pre-eclamptics at the same weeks of gestation

Fig. 6

Plasma Ang I, Ang II, and Ang-(1–7) levels in mild and severe pre-eclamptic pregnant subjects over gestation and at PP. Two-way ANOVA demonstrated an overall significant effect of weeks of gestation for plasma Ang I. For mild pre-eclamptic subjects N = 6, 14, 10, 14, 13, 14, 14; for <16, 16–20, 23–26, 27–29, 31–33, 35–37 weeks of gestation and PP, respectively. For severe pre-eclamptic subjects, N = 1, 5, 5, 4, 2, 4, 5; for <16, 16–20, 23–26, 27–29, 31–37 weeks of gestation and at PP, respectively. *p < 0.05, **p < 0.01, ***p < 001 vs. PP

Fig. 7

Urinary Ang I, Ang II, and Ang-(1–7) levels in mild and severe pre-eclamptic pregnant subjects over gestation and at PP. Two-way ANOVA demonstrated an overall significant effect of weeks of gestation for urinary Ang I and urinary Ang II. For mild pre-eclamptic subjects, N = 4, 6, 9, 11, 13, 11, 14; for <16, 16–20, 23–26, 27–29, 31–33, 35–37 weeks of gestation and at PP, respectively. For severe pre-eclamptic subjects, N = 1, 2, 5, 4, 2, 4, 3 at <16, 16–20, 23–26, 27–29, 31–37 weeks of gestation and at PP, respectively. *p < 0.05, **p < 0.01, ***p < 0.001 vs. PP