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Published in: Endocrine 2/2020

01-08-2020 | Pre-Eclampsia | Original Article

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

Authors: K. Bridget Brosnihan, David C. Merrill, Liliya M. Yamaleyeva, Kai Chen, Liomar Neves, JaNae Joyner, Courtney Givner, Kristy Lanier, Cheryl Moorefield, Brian Westwood

Published in: Endocrine | Issue 2/2020

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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.
Literature
1.
go back to reference ACOG, Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol. 133(1), e1–e25 (2019) ACOG, Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol. 133(1), e1–e25 (2019)
3.
go back to reference D.C. Merrill, M. Karoly, K. Chen, C.M. Ferrario, K.B. Brosnihan, Angiotensin-(1-7) in normal and preeclamptic pregnancy. Endocrine 18, 239–245 (2002)PubMedCrossRef D.C. Merrill, M. Karoly, K. Chen, C.M. Ferrario, K.B. Brosnihan, Angiotensin-(1-7) in normal and preeclamptic pregnancy. Endocrine 18, 239–245 (2002)PubMedCrossRef
4.
go back to reference P. August, T. Lenz, K.L. Ales, M.L. Druzin, T.G. Edersheim, J.M. Hutson et al. Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: deviations related to the development of superimposed preeclampsia. Am. J. Obstetr. Gynecol. 163, 1612–1621 (1990)CrossRef P. August, T. Lenz, K.L. Ales, M.L. Druzin, T.G. Edersheim, J.M. Hutson et al. Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: deviations related to the development of superimposed preeclampsia. Am. J. Obstetr. Gynecol. 163, 1612–1621 (1990)CrossRef
5.
go back to reference N.F. Gant, G.L. Daley, S. Chand, P.J. Whalley, P.C. MacDonald, A study of angiotensin II pressor response throughout primigravid pregnancy. J. Clin. Invest. 52, 2682–2689 (1973)PubMedPubMedCentralCrossRef N.F. Gant, G.L. Daley, S. Chand, P.J. Whalley, P.C. MacDonald, A study of angiotensin II pressor response throughout primigravid pregnancy. J. Clin. Invest. 52, 2682–2689 (1973)PubMedPubMedCentralCrossRef
6.
go back to reference G. Valdes, A.M. Germain, J. Corthorn, C. Berrios, A.C. Foradori, C.M. Ferrario et al. Urinary vasodilator and vasoconstrictor angiotensins during menstrual cycle, pregnancy, and lactation. Endocrine 16(2), 117–122 (2001)PubMedCrossRef G. Valdes, A.M. Germain, J. Corthorn, C. Berrios, A.C. Foradori, C.M. Ferrario et al. Urinary vasodilator and vasoconstrictor angiotensins during menstrual cycle, pregnancy, and lactation. Endocrine 16(2), 117–122 (2001)PubMedCrossRef
7.
go back to reference K.B. Brosnihan, P. Li, C.M. Ferrario, Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension 27(Part 2), 523–528 (1996)PubMedCrossRef K.B. Brosnihan, P. Li, C.M. Ferrario, Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension 27(Part 2), 523–528 (1996)PubMedCrossRef
8.
go back to reference G. Raffai, G. Khang, P.M. Vanhoutte, Angiotensin-(1-7) augments endothelium-dependent relaxations of porcine coronary arteries to bradykinin by inhibiting angiotensin-converting enzyme 1. J. Cardiovasc. Pharm. 63(5), 453–460 (2014)CrossRef G. Raffai, G. Khang, P.M. Vanhoutte, Angiotensin-(1-7) augments endothelium-dependent relaxations of porcine coronary arteries to bradykinin by inhibiting angiotensin-converting enzyme 1. J. Cardiovasc. Pharm. 63(5), 453–460 (2014)CrossRef
9.
go back to reference N. Jaiswal, E.A. Tallant, R.K. Jaiswal, D.I. Diz, C.M. Ferrario, Differential regulation of prostaglandin synthesis by angiotensin peptides in porcine aortic smooth muscle cells: subtypes of angiotensin receptors involved. J. Pharm. Exp. Ther. 265, 664–673 (1993) N. Jaiswal, E.A. Tallant, R.K. Jaiswal, D.I. Diz, C.M. Ferrario, Differential regulation of prostaglandin synthesis by angiotensin peptides in porcine aortic smooth muscle cells: subtypes of angiotensin receptors involved. J. Pharm. Exp. Ther. 265, 664–673 (1993)
10.
go back to reference S.Y. Osei, R.S. Ahima, R.K. Minkes, J.P. Weaver, M.C. Khosla, P.J. Kadowitz, Differential responses to angiotensin-(1-7) in the feline mesenteric and hindquarters vascular beds. Eur. J. Pharm. 234, 35–42 (1993)CrossRef S.Y. Osei, R.S. Ahima, R.K. Minkes, J.P. Weaver, M.C. Khosla, P.J. Kadowitz, Differential responses to angiotensin-(1-7) in the feline mesenteric and hindquarters vascular beds. Eur. J. Pharm. 234, 35–42 (1993)CrossRef
11.
go back to reference National High Blood Pressure Education Program NHPEP. Working group report on high blood pressure in pregnancy 1991 Report No.: 91–3029 (1991) National High Blood Pressure Education Program NHPEP. Working group report on high blood pressure in pregnancy 1991 Report No.: 91–3029 (1991)
12.
go back to reference D.S. Boeldt, I.M. Bird, Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J. Endocrinol. 232(1), R27–R44 (2017)PubMedCrossRef D.S. Boeldt, I.M. Bird, Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J. Endocrinol. 232(1), R27–R44 (2017)PubMedCrossRef
13.
go back to reference P. von Dadelszen, L.A. Magee, J.M. Roberts, Subclassification of preeclampsia. Hypertens. Pregnancy 22(2), 143–148 (2003)CrossRef P. von Dadelszen, L.A. Magee, J.M. Roberts, Subclassification of preeclampsia. Hypertens. Pregnancy 22(2), 143–148 (2003)CrossRef
14.
go back to reference K. Kohara, Y. Tabuchi, P. Senanayake, K.B. Brosnihan, C.M. Ferrario, Reassessment of plasma angiotensins measurement: effects of protease inhibitors and sample handling procedures. Peptides 12, 1135–1141 (1991)PubMedCrossRef K. Kohara, Y. Tabuchi, P. Senanayake, K.B. Brosnihan, C.M. Ferrario, Reassessment of plasma angiotensins measurement: effects of protease inhibitors and sample handling procedures. Peptides 12, 1135–1141 (1991)PubMedCrossRef
15.
go back to reference P.D. Senanayake, A. Moriguchi, H. Kumagai, D. Ganten, C.M. Ferrario, K.B. Brosnihan, Increased expression of angiotensin peptides in the brain of transgenic hypertensive rats. Peptides 15, 919–926 (1994)PubMedCrossRef P.D. Senanayake, A. Moriguchi, H. Kumagai, D. Ganten, C.M. Ferrario, K.B. Brosnihan, Increased expression of angiotensin peptides in the brain of transgenic hypertensive rats. Peptides 15, 919–926 (1994)PubMedCrossRef
16.
go back to reference P.S. Senanayake, R.R. Smeby, A.S. Martins, A. Moriguchi, H. Kumagai, D. Ganten et al. Adrenal, kidney, and heart angiotensins in female murine Ren-2 transfected hypertensive rats. Peptides 19(10), 1685–1694 (1998)PubMedCrossRef P.S. Senanayake, R.R. Smeby, A.S. Martins, A. Moriguchi, H. Kumagai, D. Ganten et al. Adrenal, kidney, and heart angiotensins in female murine Ren-2 transfected hypertensive rats. Peptides 19(10), 1685–1694 (1998)PubMedCrossRef
17.
go back to reference S.D. Sykes, K.G. Pringle, A. Zhou, G.A. Dekker, C.T. Roberts, E.R. Lumbers, Fetal sex and the circulating renin-angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension. J. Hum. Hypertens. 28(2), 133–139 (2014)PubMedCrossRef S.D. Sykes, K.G. Pringle, A. Zhou, G.A. Dekker, C.T. Roberts, E.R. Lumbers, Fetal sex and the circulating renin-angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension. J. Hum. Hypertens. 28(2), 133–139 (2014)PubMedCrossRef
18.
go back to reference B. Langer, M. Grima, C. Coquard, A.M. Bader, G. Schlaeder, J.L. Imbs, Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia. Obstet. Gynecol. 91(2), 196–202 (1998)PubMedCrossRef B. Langer, M. Grima, C. Coquard, A.M. Bader, G. Schlaeder, J.L. Imbs, Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia. Obstet. Gynecol. 91(2), 196–202 (1998)PubMedCrossRef
19.
go back to reference M.A. Brown, J. Wang, J.A. Whitworth, The renin-angiotensin-aldosterone system in pre-eclampsia. Clin. Exp. Hypertension 19(5–6), 713–726 (1997).CrossRef M.A. Brown, J. Wang, J.A. Whitworth, The renin-angiotensin-aldosterone system in pre-eclampsia. Clin. Exp. Hypertension 19(5–6), 713–726 (1997).CrossRef
20.
go back to reference E.P. Velloso, R. Vieira, A.C. Cabral, E. Kalapothakis, R.A. Santos, Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype. Braz. J. Med. Biol. Res. 40(4), 583–590 (2007)PubMedCrossRef E.P. Velloso, R. Vieira, A.C. Cabral, E. Kalapothakis, R.A. Santos, Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype. Braz. J. Med. Biol. Res. 40(4), 583–590 (2007)PubMedCrossRef
21.
go back to reference Y.P. Chen, Y.P. Lu, J. Li, Z.W. Liu, W.J. Chen, X.J. Liang et al. Fetal and maternal angiotensin (1-7) are associated with preterm birth. J. Hypertens. 32(9), 1833–1841 (2014)PubMedCrossRef Y.P. Chen, Y.P. Lu, J. Li, Z.W. Liu, W.J. Chen, X.J. Liang et al. Fetal and maternal angiotensin (1-7) are associated with preterm birth. J. Hypertens. 32(9), 1833–1841 (2014)PubMedCrossRef
22.
go back to reference G. Wallukat, V. Homuth, T. Fischer, C. Lindschau, B. Horstkamp, A. Jupner et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J. Clin. Investig. 103(7), 945–952 (1999)PubMedCrossRef G. Wallukat, V. Homuth, T. Fischer, C. Lindschau, B. Horstkamp, A. Jupner et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J. Clin. Investig. 103(7), 945–952 (1999)PubMedCrossRef
23.
go back to reference E.R. Lumbers, K.G. Pringle, Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306(2), R91–R101 (2014)PubMedCrossRef E.R. Lumbers, K.G. Pringle, Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306(2), R91–R101 (2014)PubMedCrossRef
24.
go back to reference K.D. Burns, Y. Lytvyn, F.H. Mahmud, D. Daneman, L. Deda, D.B. Dunger et al. The relationship between urinary renin-angiotensin system markers, renal function, and blood pressure in adolescents with type 1 diabetes. Am. J. Physiol. Ren. Physiol. 312(2), F335–F342 (2017)CrossRef K.D. Burns, Y. Lytvyn, F.H. Mahmud, D. Daneman, L. Deda, D.B. Dunger et al. The relationship between urinary renin-angiotensin system markers, renal function, and blood pressure in adolescents with type 1 diabetes. Am. J. Physiol. Ren. Physiol. 312(2), F335–F342 (2017)CrossRef
25.
go back to reference K.G. Pringle, S.D. Sykes, E.R. Lumbers, Circulating and intrarenal renin-angiotensin systems in healthy men and nonpregnant women. Physiol. Rep. 3(10), e2586 e1–10 (2015)CrossRef K.G. Pringle, S.D. Sykes, E.R. Lumbers, Circulating and intrarenal renin-angiotensin systems in healthy men and nonpregnant women. Physiol. Rep. 3(10), e2586 e1–10 (2015)CrossRef
26.
go back to reference H. Kobori, A. Nishiyama, L.M. Harrison-Bernard, L.G. Navar, Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension. Hypertension 41(1), 42–49 (2003)PubMedPubMedCentralCrossRef H. Kobori, A. Nishiyama, L.M. Harrison-Bernard, L.G. Navar, Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension. Hypertension 41(1), 42–49 (2003)PubMedPubMedCentralCrossRef
27.
go back to reference E.R. Lumbers, S.L. Skinner, The occurrence and assay of renin in human urine. Aust. J. Exp. Biol. Med Sci. 47(2), 251–262 (1969)PubMedCrossRef E.R. Lumbers, S.L. Skinner, The occurrence and assay of renin in human urine. Aust. J. Exp. Biol. Med Sci. 47(2), 251–262 (1969)PubMedCrossRef
28.
go back to reference J. Wysocki, A. Goodling, M. Burgaya, K. Whitlock, J. Ruzinski, D. Batlle et al. Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease. Am. J. Physiol. Ren. Physiol. 313(2), F487–F494 (2017)CrossRef J. Wysocki, A. Goodling, M. Burgaya, K. Whitlock, J. Ruzinski, D. Batlle et al. Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease. Am. J. Physiol. Ren. Physiol. 313(2), F487–F494 (2017)CrossRef
29.
go back to reference C.M. Ferrario, N. Martell, C. Yunis, J.M. Flack, M.C. Chappell, K.B. Brosnihan et al. Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects. Am. J. Hypertens. 11, 137–146 (1998)PubMedCrossRef C.M. Ferrario, N. Martell, C. Yunis, J.M. Flack, M.C. Chappell, K.B. Brosnihan et al. Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects. Am. J. Hypertens. 11, 137–146 (1998)PubMedCrossRef
30.
go back to reference J. Joyner, L.A. Neves, K. Stovall, C.M. Ferrario, K.B. Brosnihan, Angiotensin-(1-7) serves as an aquaretic by increasing water intake and diuresis in association with downregulation of aquaporin-1 during pregnancy in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294(3), R1073–R1080 (2008)PubMedCrossRef J. Joyner, L.A. Neves, K. Stovall, C.M. Ferrario, K.B. Brosnihan, Angiotensin-(1-7) serves as an aquaretic by increasing water intake and diuresis in association with downregulation of aquaporin-1 during pregnancy in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294(3), R1073–R1080 (2008)PubMedCrossRef
31.
go back to reference L.M. Yamaleyeva, D.C. Merrill, T.J. Ebert, T.L. Smith, H.L. Mertz, K.B. Brosnihan, Hemodynamic responses to angiotensin-(1-7) in women in their third trimester of pregnancy. Hypertens Pregnancy 33, 375–388 (2014)PubMedCrossRef L.M. Yamaleyeva, D.C. Merrill, T.J. Ebert, T.L. Smith, H.L. Mertz, K.B. Brosnihan, Hemodynamic responses to angiotensin-(1-7) in women in their third trimester of pregnancy. Hypertens Pregnancy 33, 375–388 (2014)PubMedCrossRef
32.
go back to reference G. Valdes, P. Kaufmann, J. Corthorn, R. Erices, K.B. Brosnihan, J. Joyner-Grantham, Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod. Biol. Endocrinol. 7(1), 27–79 (2009)CrossRef G. Valdes, P. Kaufmann, J. Corthorn, R. Erices, K.B. Brosnihan, J. Joyner-Grantham, Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod. Biol. Endocrinol. 7(1), 27–79 (2009)CrossRef
33.
go back to reference E.R. Lumbers, Peripheral vascular reactivity to angiotensin and noradrenaline in pregnant and non-pregnant women. Aust. J. Exp. Biol. Med Sci. 48(5), 493–500 (1970)PubMedCrossRef E.R. Lumbers, Peripheral vascular reactivity to angiotensin and noradrenaline in pregnant and non-pregnant women. Aust. J. Exp. Biol. Med Sci. 48(5), 493–500 (1970)PubMedCrossRef
34.
go back to reference L. Malha, C.P. Sison, G. Helseth, J.E. Sealey, P. August, Renin-angiotensin-aldosterone profiles in pregnant women with chronic hypertension. Hypertension 72(2), 417–424 (2018)PubMedPubMedCentralCrossRef L. Malha, C.P. Sison, G. Helseth, J.E. Sealey, P. August, Renin-angiotensin-aldosterone profiles in pregnant women with chronic hypertension. Hypertension 72(2), 417–424 (2018)PubMedPubMedCentralCrossRef
Metadata
Title
Longitudinal study of angiotensin peptides in normal and pre-eclamptic pregnancy
Authors
K. Bridget Brosnihan
David C. Merrill
Liliya M. Yamaleyeva
Kai Chen
Liomar Neves
JaNae Joyner
Courtney Givner
Kristy Lanier
Cheryl Moorefield
Brian Westwood
Publication date
01-08-2020
Publisher
Springer US
Keyword
Pre-Eclampsia
Published in
Endocrine / Issue 2/2020
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-020-02296-3

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