Fetal programming and the angiotensin-(1-7) axis: a review of the experimental and clinical data

Abstract

Hypertension is the primary risk factor for cardiovascular disease that constitutes a serious worldwide health concern and a significant healthcare burden. As the majority of hypertension has an unknown etiology, considerable research efforts in both experimental models and human cohorts has focused on the premise that alterations in the fetal and perinatal environment are key factors in the development of hypertension in children and adults. The exact mechanisms of how fetal programming events increase the risk of hypertension and cardiovascular disease are not fully elaborated; however, the focus on alterations in the biochemical components and functional aspects of the renin-angiotensin (Ang) system (RAS) has predominated, particularly activation of the Ang-converting enzyme (ACE)-Ang II-Ang type 1 receptor (AT1R) axis. The emerging view of alternative pathways within the RAS that may functionally antagonize the Ang II axis raise the possibility that programming events also target the non-classical components of the RAS as an additional mechanism contributing to the development and progression of hypertension. In the current review, we evaluate the potential role of the ACE2-Ang-(1-7)-Mas receptor (MasR) axis of the RAS in fetal programming events and cardiovascular and renal dysfunction. Specifically, the review examines the impact of fetal programming on the Ang-(1-7) axis within the circulation, kidney, and brain such that the loss of Ang-(1-7) expression or tone, contributes to the chronic dysregulation of blood pressure (BP) and cardiometabolic disease in the offspring, as well as the influence of sex on potential programming of this pathway.

Keywords: ACE; angiotensin converting enzyme 2; angiotensin-(1-7); fetal programming.

Conflict of interest statement

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Figures

Figure 1.. Programming events may contribute to the development of hypertension and cardiovascular disease by attenuating the ACE2-Ang-(1–7)-MasR-NO axis

Fetal programming targets components of the Ang-(1–7) axis in the circulation, kidney, and brain that may contribute to the chronic dysregulation of BP and autonomic function leading to hypertension and cardiovascular disease. Based on a model of antenatal glucocorticoid exposure in sheep and a cohort of young adults born preterm, our studies suggest that programming reduces ACE2 (−) and enhances the ratio of ACE to ACE2 (+) and the ratio of Ang II to Ang-(1–7) (+) in the circulation and brain. Programming events also reduce expression of the MasR (−) in brain and kidney that is associated with reduced Na+ excretion, lower nitric oxide (NO) tone, and higher MAPK stimulation as well as attenuated baroreflex sensitivity (BRS).

Figure 2.. Processing pathways for Ang II and Ang-(1–7)

The precursor angiotensinogen is cleaved by renin to Ang I. Ang I is hydrolyzed by Ang-converting enzyme (ACE) to Ang II which binds to the AT1R to stimulate reactive oxygen species (ROS), but reduce nitric oxide (NO). Alternatively, Ang I is hydrolyzed by neprilysin directly to Ang-(1–7) or Ang II is cleaved by ACE2 to form Ang-(1–7) that binds to the MasR to stimulate NO and reduce ROS. ACE degrades Ang-(1–7) to Ang-(1–5) while dipeptidyl peptidase 3 (DPP3) hydrolyzes Ang-(1–7) to Ang-(3–7) and then Ang-(3–7) to Ang-(5–7). Note the figure does not depict the binding of Ang II/Ang III or potential interaction of Ang-(1–7) with the AT2R or bradykinin B2R. Adapted from Chappell [15].

Figure 3.. Betamethasone exposure influences the circulating Ang system in adult male sheep

(A) Circulating ACE2 activity is significantly reduced in antenatal BMX adult male sheep compared with controls; serum ACE activity is significantly higher than ACE2 in adult male BMX but not control male sheep. Inset: The ACE to ACE2 activity ratio significantly correlated to mean arterial pressure (MAP) in adult BMX and control male sheep; shown are the correlation coefficient with P-value and regression line with 95% confidence limits. (B) The Ang II to Ang-(1–7) ratio is higher in the plasma of adult male BMX sheep compared with controls. Data are means ±S.E.M. with *P≤0.05 by two-way ANOVA. ACE and ACE2 data adapted from Shaltout et al. [47]. Peptide measurements in (B) from plasma of adult male control (n=6) and BMX (n=5) sheep using separate RIAs for Ang I, Ang II, and Ang-(1–7) with *P≤0.05 by unpaired Student’s t test (Chappell, unpublished data).

Figure 4.. Sodium uptake in isolated proximal tubule cells of female and male controls and BMX sheep

Isolated proximal tubule cells (PTCs) from unexposed (Control) and BMX sheep were maintained in primary cultures for 10 days and the uptake of sodium (Na+) was evaluated by Na+ green fluorescence. (A) Basal Na+ uptake was higher in Control male compared with female PTCs. Ang-(1–7) (Ang7, 1 pM) inhibited Na+ uptake in Control male and female PTCs. The NO donor SNAP (100 μM) and the stable analog 8-bromo-cGMP (GMP, 1 μM) also inhibited Na+ uptake in both Control male and female PTCs. (B) Basal Na+ uptake was higher in BMX male compared with BMX female PTCs. Treatment with Ang7, SNAP and GMP reduced Na+ uptake in BMX female, but failed to reduce Na+ in BMX male PTCs. Data are mean ± S.E.M.; *P≤0.05 compared with males; #P≤0.05 compared with Basal Females; †P≤0.05 compared with Basal Males by two-way ANOVA. Adapted from Su et al. [62].

Figure 5.. BMX influences the brain Ang system in adult sheep

(A) Dorsomedial medullary expression of angiotensinogen (Aogen) protein is higher in BMX sheep. (B) Peptide ratios of Ang II to Ang I and Ang II to Ang-(1–7) (Ang7) are higher in dorsomedial medulla of BMX sheep. (C) MasR protein expression is lower in dorsomedial medulla of BMX sheep at 0.5 and 1.8 years of age. (D) ACE2 protein expression (120 kDa) is lower in dorsal medulla of BMX sheep. All data are mean ±S.E.M.; *P≤0.05 compared with BMX; **P≤0.01 compared with BMX by unpaired Student’s t test. Data in panels (A–C) are adapted from Marshall et al. [30]. Data in (D) are ratio of ACE2 to total protein of the immunoblot as adapted from Hendricks et al. [74].

Figure 6.. Placental expression of Angs and neprilysin activity in wild-type and ACE2 knockout mice

Quantitation of Ang I (A), Ang II (B), Ang-(1–7) (C), and neprilysin activity (D) in the placenta of C57Bl/6 (wild-type, WT) and ACE2 knockout (KO) mice. All data are mean ±S.E.M.; *P≤0.05 compared with WT by unpaired Student’s t test. Adapted from Bharadwaj et al. [77].

Figure 7.. Perinatal programming of the circulatory RAS resulting in reduced Ang-(1–7) is greatest in female adolescents and in adolescents with overweight/obesity at age 14 years

(A) The preterm-term birth difference in plasma Ang-(1–7) at age 14 years is significantly greater in female adolescents (preterm n=70, term n=23) compared with male adolescents (preterm n=50, term n=20); **P≤0.001 for female preterm-term birth comparison and *P≤0.05 for male preterm-term birth comparison. (B) The preterm-term birth difference in the ratio of plasma Ang II to Ang-(1–7) is significantly greater in adolescents with overweight/obesity (OWO; preterm n=42, term n=13; **P≤0.01) compared with adolescents with body mass index (BMI) < 85th percentile (preterm n=78, term n=30; *P<0.08); amongst adolescents born preterm, the ratio of plasma Ang II to Ang-(1–7) is significantly higher in subjects with OWO compared with BMI < 85th percentile (#P≤0.001) but not in term-born subjects. Analysis is between-group comparisons via the Wilcoxon’s rank-sum test. Bars = median, large circles = mean, boxes = interquartile ranges, whiskers = ≤ 1.5 × IQR. Data are adapted from South et al. [102].

Figure 8.. The blood pressure-renal Ang-(1–7) relationship is blunted in patients born preterm as compared with those born at term

(A,B) Urine Ang-(1–7) corrected for urine creatinine (Cr) at 14 years of age inversely correlates with systolic blood pressure (SBP) measured at 14 years of age in Term (solid line, n=50; P=0.07) but not Preterm adolescents (dashed line, n=175; P=0.98). (C,D) Urine Ang-(1–7)/Cr at 14 years of age predicts SBP at 19 years of age in Term (solid line, n=34; P=0.004) but not Preterm young adults (dashed line, n=139; P=0.98). Urine Ang-(1–7)/Cr is naturally log transformed. Pearson correlation coefficients with corresponding P-values and regression lines with 95% confidence limits are shown (South, unpublished data).