Spontaneously occurring differences in fetal weight do not affect blood pressure, the hypothalamic–pituitary–adrenal axis or the renin–angiotensin system in the late-gestation ovine fetus
Megan E. Probyn A C , Victoria Stacy A , Mina Desai B , Michael Ross B and Richard Harding AA Department of Anatomy and Developmental Biology, Monash University, Vic. 3800, Australia.
B Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, CA 90509, USA.
C Corresponding author. Email: m.probyn@uq.edu.au
Reproduction, Fertility and Development 20(4) 451-459 https://doi.org/10.1071/RD07198
Submitted: 26 October 2007 Accepted: 20 January 2008 Published: 11 April 2008
Abstract
Fetal growth restriction (FGR) has been associated with an increased incidence of cardiovascular disease in adult life. Animal models of restricted fetal growth often cause FGR over discrete periods of gestation and hence may not be applicable to individuals with low birthweight but who are not clinically growth-restricted. Our aim was to determine whether spontaneously occurring differences in fetal growth influence the functional development of the hypothalamic–pituitary–adrenal (HPA) axis or the renin–angiotensin system (RAS), both of which are involved in arterial pressure regulation. Using sheep, arterial pressure and heart rate were monitored in chronically catheterised singleton and twin fetuses at 130, 134 and 137 days of gestation (term ~147 days). Fetuses were challenged, at different times, with exogenous angiotensin (Ang) II, combined administration of arginine vasopressin and corticotrophin releasing hormone (AVP+CRH) and adrenocorticotrophic hormone (ACTH); fetal cardiovascular responses and circulating cortisol concentrations were measured. In all fetuses Ang II and AVP+CRH altered cardiovascular function (increase in mean arterial pressure and decrease in heart rate); both AVP+CRH and ACTH increased circulating cortisol concentrations. Responses were not related to fetal bodyweight. We conclude that naturally occurring differences in growth do not influence the development of the HPA axis or RAS function in fetal sheep.
Additional keywords: arterial pressure, cortisol.
Acknowledgements
We are grateful for the assistance of Sally Gregg, Natasha Blash, Nadine Brew, Alex Satragno (animal care), Andrew Jefferies (electrolyte measurements) and Jan Loose (cortisol assay). Funding was provided by the National Health and Medical Research Council of Australia, and Harbor-UCLA Medical Center.
Alexander, B. T. (2003). Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension 41, 457–462.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Barker, D. J. (1995). Fetal origins of coronary heart disease. BMJ 311, 171–174.
| PubMed |
Barker, D. J. , Gluckman, P. D. , Godfrey, K. M. , Harding, J. E. , Owens, J. A. , and Robinson, J. S. (1993). Fetal nutrition and cardiovascular disease in adult life. Lancet 341, 938–941.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Bocking, A. D. , McMillen, I. C. , Harding, R. , and Thorburn, G. D. (1986). Effect of reduced uterine blood flow on fetal and maternal cortisol. J. Dev. Physiol. 8, 237–245.
| PubMed |
Bubb, K. J. , Cock, M. L. , Black, M. J. , Dodic, M. , Boon, W. M. , Parkington, H. C. , Harding, R. , and Tare, M. (2007). Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep. J. Physiol. 578, 871–881.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Edwards, L. J. , and McMillen, I. C. (2001). Maternal undernutrition increases arterial blood pressure in the sheep fetus during late gestation. J. Physiol. 533, 561–570.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Edwards, L. J. , and McMillen, I. C. (2002). Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R669–R679.
| PubMed |
Edwards, L. J. , Simonetta, G. , Owens, J. A. , Robinson, J. S. , and McMillen, I. C. (1999). Restriction of placental and fetal growth in sheep alters fetal blood pressure responses to angiotensin II and captopril. J. Physiol. 515((Pt 3)), 897–904.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Edwards, L. J. , Bryce, A. E. , Coulter, C. L. , and McMillen, I. C. (2002). Maternal undernutrition throughout pregnancy increases adrenocorticotrophin receptor and steroidogenic acute regulatory protein gene expression in the adrenal gland of twin fetal sheep during late gestation. Mol. Cell. Endocrinol. 196, 1–10.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Gilbert, J. S. , Lang, A. L. , and Nijland, M. J. (2005). Maternal nutrient restriction and the fetal left ventricle: decreased angiotensin receptor expression. Reprod. Biol. Endocrinol. 3, 27.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Hawkins, P. , Steyn, C. , McGarrigle, H. H. , Saito, T. , Ozaki, T. , Stratford, L. L. , Noakes, D. E. , and Hanson, M. A. (1999). Effect of maternal nutrient restriction in early gestation on development of the hypothalamic–pituitary–adrenal axis in fetal sheep at 0.8–0.9 of gestation. J. Endocrinol. 163, 553–561.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Langley-Evans, S. C. , Phillips, G. J. , and Jackson, A. A. (1994). In utero exposure to maternal low-protein diets induces hypertension in weanling rats, independently of maternal blood pressure changes. Clin. Nutr. 13, 319–324.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Langley-Evans, S. C. , Welham, S. J. , and Jackson, A. A. (1999). Fetal exposure to a maternal low-protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 64, 965–974.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Lesage, J. , Blondeau, B. , Grino, M. , Breant, B. , and Dupouy, J. P. (2001). Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo–pituitary–adrenal axis in the newborn rat. Endocrinology 142, 1692–1702.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Louey, S. , Cock, M. L. , Stevenson, K. M. , and Harding, R. (2000). Placental insufficiency and fetal growth restriction lead to postnatal hypotension and altered postnatal growth in sheep. Pediatr. Res. 48, 808–814.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
McMillen, I. C. , and Robinson, J. S. (2005). Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol. Rev. 85, 571–633.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
McMillen, I. C. , Adams, M. B. , Ross, J. T. , Coulter, C. L. , Simonetta, G. , Owens, J. A. , Robinson, J. S. , and Edwards, L. J. (2001). Fetal growth restriction: adaptations and consequences. Reproduction 122, 195–204.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Min, S. J. , Luke, B. , Gillespie, B. , Min, L. , Newman, R. B. , Mauldin, J. G. , Witter, F. R. , Salman, F. A. , and O’Sullivan, M. J. (2000). Birthweight references for twins. Am. J. Obstet. Gynecol. 182, 1250–1257.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Muggli, E. E. , and Halliday, J. L. (2007). Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006. Med. J. Aust. 186, 243–248.
| PubMed |
Payne, J. A. , Alexander, B. T. , and Khalil, R. A. (2004). Decreased endothelium-dependent NO-cGMP vascular relaxation and hypertension in growth-restricted rats on a high-salt diet. Hypertension 43, 420–427.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Phillips, I. D. , Simonetta, G. , Owens, J. A. , Robinson, J. S. , Clarke, I. J. , and McMillen, I. C. (1996). Placental restriction alters the functional development of the pituitary–adrenal axis in the sheep fetus during late gestation. Pediatr. Res. 40, 861–866.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Poore, K. R. , Young, I. R. , Canny, B. J. , and Thorburn, G. D. (1998). Studies on the role of ACTH in the regulation of adrenal responsiveness and the timing of parturition in the ovine fetus. J. Endocrinol. 158, 161–171.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Whorwood, C. B. , Firth, K. M. , Budge, H. , and Symonds, M. E. (2001). Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 142, 2854–2864.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Woodall, S. M. , Johnston, B. M. , Breier, B. H. , and Gluckman, P. D. (1996). Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr. Res. 40, 438–443.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Woods, L. L. , Weeks, D. A. , and Rasch, R. (2004). Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int. 65, 1339–1348.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zhang, D. Y. , Lumbers, E. R. , Simonetta, G. , Wu, J. J. , Owens, J. A. , Robinson, J. S. , and McMillen, I. C. (2000). Effects of placental insufficiency on the ovine fetal renin–angiotensin system. Exp. Physiol. 85, 79–84.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zohdi, V. , Moritz, K. M. , Bubb, K. J. , Cock, M. L. , Wreford, N. , Harding, R. , and Black, M. J. (2007). Nephrogenesis and the renal renin–angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1267–R1273.
| PubMed |
