BJOG. 2015 Aug;122(9):1236-43. doi: 10.1111/1471-0528.13397.

Effects of pre-eclampsia and fetal growth restriction on C-type natriuretic peptide.

Espiner EA1, Prickett TC1, Taylor RS2, Reid RA3, McCowan LM2.
  • 1Department of Medicine, University of Otago, Christchurch, New Zealand.
  • 2Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
  • 3Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand.

 

Abstract

OBJECTIVE: To determine changes in plasma C-type natriuretic peptide (CNP), a paracrine product of the vascular endothelium, in pregnancies with vascular disorders, and relate these to time of presentation and severity.

DESIGN: Retrospective nested cases and controls.

SETTING: Community study, Auckland New Zealand.

POPULATION: Screening for Pregnancy Endpoints (SCOPE) data and bio-bank of maternal plasma.

METHODS: Maternal plasma amino terminal proCNP (NTproCNP) was measured by radioimmunoassay in early (14-16 weeks of gestation, and again at 19-21 weeks of gestation) and late (34-36 weeks of gestation) pregnancy in three groups of women (20 per group): pre-eclampsia (pre-eclampsia); gestational hypertension (GHT) with small for gestational age (SGA); and uncomplicated pregnancy.

MAIN OUTCOME MEASURES: Change in NTproCNP and associations with concurrent blood pressure, time of case presentation, severity, and infant birthweight.

RESULTS: Plasma NTproCNP in early pregnancy in women with vascular disorders did not differ from those found in controls. In late pregnancy, levels in pre-eclampsia (28.8 ± 2.3 pM) and in GHT with SGA (28.6 ± 4.8 pM) were significantly increased (P = 0.01 and 0.027, respectively) compared with controls (21.3 ± 1 pM). In pre-eclampsia, levels were significantly higher (P < 0.03) at 14-16 weeks of gestation in women diagnosed prior to 34 weeks of gestation. Combining all three groups, associations of NTproCNP with concurrent diastolic and mean arterial pressure were found at 34-36 weeks of gestation (r = 0.46). No significant associations were identified with birthweight.

CONCLUSIONS: CNP secretion during gestation is responsive to vascular stress. Plasma NTproCNP measurements may have clinical application in late pregnancy in defining the different phenotypes associated with pre-eclampsia.

KEYWORDS: Fetal growth restriction; NTproCNP; hypertension; pre-eclampsia; pregnancy; small for gestational age

PMID: 25846957

 

Supplement:   (Contributed by Eric Espiner and Tim Prickett)

C-type Natriuretic Peptide (CNP) belongs to a family of peptides best known for their role in the regulation of blood pressure and salt balance [1]. In contrast to the cardiac peptides Atrial (ANP) and B type (BNP) natriuretic peptides, CNP is widely expressed in a range of tissues including the vascular endothelium, has no natriuretic action, and is barely detectable in healthy human adult plasma. Studies in experimental animals clearly show that CNP has important vasoprotective functions including anti- inflammatory, anti- thrombotic and anti- proliferative actions in intimal tissues [2]. Whether such findings apply in humans is unclear, and made difficult to assess in vivo by the largely paracrine (local) nature of CNP’s regulation and actions.

Defining CNP’s regulation in humans has been facilitated by the discovery [3] that a bio inactive fragment of the prohormone synthetized in tissues (amino terminal proCNP, NTproCNP) – in contrast to bio active CNP forms – is not degraded at source (Figure 1) and enters the circulation where it can be easily measured. Plasma concentrations of NTproCNP therefore reflect CNP production in tissues provided renal function is normal. In keeping with the critical role of CNP in stimulating endochondral bone growth [4], plasma NTproCNP concentrations are strongly linked to skeletal growth velocity in children [5] but levels stablise in adults once the growth plates in long bones atrophy [6]. Study in adults aged 20-80yr in the community show that levels are higher in men, rise progressively after the 4th decade and are positively associated with vascular risk factors, including hypertension [6].

 

Figure 1-1

Figure 1. Processing pathway of proCNP. CNP is synthetized as a precursor (proCNP 1-103) which is cleaved intracellularly just prior to secretion, releasing the (carboxy-terminal) bioactive peptide (CNP 53, ie proCNP 51-103) and an amino terminal peptide fragment, NTproCNP (proCNP 1-50). CNP 53 is further processed at unknown sites yielding a smaller peptide (CNP 22, ie proCNP 82-103). Peptides retaining the 17 amino acid ring (shown in black) have biological activity but are rapidly degraded at source.

 

The current findings in human pregnancy for the first time directly link sequential changes in maternal plasma NTproCNP with blood pressure elevations and vascular complications. Notably maternal plasma NTproCNP levels were significantly increased as early as 14-16 weeks gestational age (GA) in women developing the most severe form of pre-eclampsia where diagnosis was confirmed before 34 weeks (Figure 2). Larger prospective studies are now required to evaluate possible diagnostic applications of NTproCNP in human pregnancy. A number of factors other than systemic arterial pressure are likely to contribute to increasing levels both in women with complicated pregnancies [7] and during normal gestation. For example, younger maternal age, nulliparity, and twinning are positively associated with NTproCNP after 24 weeks gestation. Unravelling the underlying mechanisms linking these changes will require defining not only the specific stimuli and source of CNP secretion but in addition the functions CNP subserves in maintaining fetal maternal welfare. Plausible hypotheses include an adaptive response within the maternal circulation to increases in vascular load, increase in shear stress [8] (a well-documented stimulus to CNP gene expression [9]) and/or part of an efferent response to threatened substrate supply detected by fetal placental tissues. Clearly resolving these questions will require larger prospective studies in humans and interventional studies in experimental animals. Relevant here are our findings in uncomplicated ovine pregnancy where there is strong evidence that CNP is highly regulated [10]. Although placentation and the dynamics of fetal growth differ in the two species, findings from ovine pregnancy often have direct application to human pregnancy [11]. In contrast to human pregnancy, ovine maternal plasma concentrations of both CNP and NTproCNP rise abruptly at the time of accelerated placental growth – and remain elevated (compared to levels in non-pregnant sheep) until just before parturition[12]. Litter size or nutrient restriction augment maternal concentrations of CNP peptides [10, 13], suggesting that both increased demand for energy substrate and restricted supply are important stimuli in ovine pregnancy. In sheep [14] but not in human pregnancy [7], the placenta itself is a major source of the high maternal levels in plasma but in neither species is there evidence for transfer of CNP peptides to the fetus. Importantly, others have shown that the CNP receptor (NPRB) and CNP protein are both selectively increased in the ovine uterine arterial vessel wall in late gestation-changes that do not occur in the renal or mesenteric vessels [15]. These findings, which align with vasoprotective actions of CNP and its role in promoting angiogenesis and blood flow [16], suggest that CNP may be a significant contributor to the greatly increased uterine blood flow associated with gestation in normal sheep. Moreover, since nutrient restriction in sheep impairs placental blood flow [17], the sustained increase we observe in maternal plasma NTproCNP levels during modest nutrient restriction [13] fits with an adaptive response directed to improving the supply of nutrients to the fetus. Once a specific and effective antagonist to CNP intracellular signally becomes available, it should be possible to test these hypotheses now that the dynamics of changing plasma levels in pregnancy are more clearly defined.

But do findings in ovine pregnancy clarify CNP’s role in human pregnancy? On present evidence the uniquely high circulating maternal levels of CNP peptides observed in sheep are likely to be significant in meeting the high demands for nutrients imposed by rapid fetal growth in ovine pregnancy (combined birth weight 1-8kg, mean 4kg over gestation of 145 days) – much more demanding on substrate supply than required for growth of the human fetus. However when there are constraints, as may occur with vascular complications in human gestation, we postulate that an adaptive increase in maternal NTproCNP occurs – not sourced from the placenta but more likely from the uterine vasculature, as documented in normal ovine gestation. Answers to these important questions – with possible therapeutic applications – are more than academic now that CNP agonists are available and already approved (ClinicalTrials.govNCT02055157) for use in children with specific disorders of bone growth.

 

Figure 2

Figure 2   Plasma NTproCNP concentrations (A) and mean arterial pressure (B) at 15 weeks gestation in women who subsequently present with either early or late onset pre-eclampsia.

 

References

  1. Potter, L.R., S. Abbey-Hosch, and D.M. Dickey (2006) Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 27: 47-72.
  2. Qian, J.Y., A. Haruno, Y. Asada, T. Nishida, Y. Saito, T. Matsuda, and H. Ueno (2002) Local expression of C-type natriuretic peptide suppresses inflammation, eliminates shear stress-induced thrombosis, and prevents neointima formation through enhanced nitric oxide production in rabbit injured carotid arteries. Circ Res 91: 1063-1069.
  3. Prickett, T.C.R., T.G. Yandle, M.G. Nicholls, E.A. Espiner, and A.M. Richards (2001) Identification of amino-terminal pro-C-type natriuretic peptide in human plasma. Biochem Biophys Res Commun 286: 513-517.
  4. Olney, R.C. (2006) C-type natriuretic peptide in growth: a new paradigm. Growth Horm IGF Res 16 Suppl A: S6-14.
  5. Olney, R.C., J.W. Permuy, T.C. Prickett, J.C. Han, and E.A. Espiner (2012) Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children. Clin Endocrinol (Oxf) 77: 416-422.
  6. Prickett, T.C., R.C. Olney, V.A. Cameron, M.J. Ellis, A.M. Richards, and E.A. Espiner (2013) Impact of age, phenotype and cardio-renal function on plasma C-type and B-type natriuretic peptide forms in an adult population. Clin Endocrinol (Oxf) 78: 783-9.
  7. Reid, R.A., T.C. Prickett, B.E. Pullar, B.A. Darlow, J.E. Gullam, and E.A. Espiner (2014) C-type natriuretic peptide in complicated pregnancy: increased secretion precedes adverse events. J Clin Endocrinol Metab 99: 1470-8.
  8. Sprague, B., N.C. Chesler, and R.R. Magness (2010) Shear stress regulation of nitric oxide production in uterine and placental artery endothelial cells: experimental studies and hemodynamic models of shear stresses on endothelial cells. Int J Dev Biol 54: 331-9.
  9. Chun, T.H., H. Itoh, Y. Ogawa, N. Tamura, K. Takaya, T. Igaki, J. Yamashita, K. Doi, M. Inoue, K. Masatsugu, R. Korenaga, J. Ando, and K. Nakao (1997) Shear stress augments expression of C-type natriuretic peptide and adrenomedullin. Hypertension 29: 1296-302.
  10. Prickett, T.C., C.W. Rumball, A.J. Buckley, F.H. Bloomfield, T.G. Yandle, J.E. Harding, and E.A. Espiner (2007) C-type natriuretic peptide forms in the ovine fetal and maternal circulations: evidence for independent regulation and reciprocal response to undernutrition. Endocrinology 148: 4015-22.
  11. Barry, J.S. and R.V. Anthony (2008) The pregnant sheep as a model for human pregnancy. Theriogenology 69: 55-67.
  12. McNeill, B.A., G.K. Barrell, M. Wellby, T.C. Prickett, T.G. Yandle, and E.A. Espiner (2009) C-type natriuretic peptide forms in pregnancy: maternal plasma profiles during ovine gestation correlate with placental and fetal maturation. Endocrinology 150: 4777-83.
  13. Madhavan, S., T.C. Prickett, E.A. Espiner, and G.K. Barrell (2015) Nutrient restriction in early ovine pregnancy stimulates C-type natriuretic peptide production. Reprod Fertil Dev doi: 10.1071/RD15192.
  14. McNeill, B.A., G.K. Barrell, F.B. Wooding, T.C. Prickett, and E.A. Espiner (2011) The trophoblast binucleate cell is the source of maternal circulating C-type natriuretic peptide during ovine pregnancy. Placenta 32: 645-50.
  15. Itoh, H., I.M. Bird, K. Nakao, and R.R. Magness (1998) Pregnancy increases soluble and particulate guanylate cyclases and decreases the clearance receptor of natriuretic peptides in ovine uterine, but not systemic, arteries. Endocrinology 139: 3329-41.
  16. Yamahara, K., H. Itoh, T.H. Chun, Y. Ogawa, J. Yamashita, N. Sawada, Y. Fukunaga, M. Sone, T. Yurugi-Kobayashi, K. Miyashita, H. Tsujimoto, H. Kook, R. Feil, D.L. Garbers, F. Hofmann, and K. Nakao (2003) Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc Natl Acad Sci U S A 100: 3404-9.
  17. Vonnahme, K.A. (2012) How the maternal environment impacts fetal and placental development: implications for livestock production. Anim Reprod 9: 789-797.

 

OLYMPUS DIGITAL CAMERAContact:

Eric Espiner MD

Department of Medicine

University of Otago, Christchurch, New Zealand

eric.espiner@otago.ac.nz

 

 

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