Restriction of placental function alters heart development in the sheep fetus
Abstract
Placental insufficiency, resulting in restriction of fetal substrate supply, is a major cause of intrauterine growth restriction (IUGR) and increased neonatal morbidity. Fetal adaptations to placental restriction maintain the growth of key organs, including the heart, but the impact of these adaptations on individual cardiomyocytes is unknown. Placental and hence fetal growth restriction was induced in fetal sheep by removing the majority of caruncles in the ewe before mating (placental restriction, PR). Vascular surgery was performed on 13 control and 11 PR fetuses at 110–125 days of gestation (term: 150 ± 3 days). PR fetuses with a mean gestational Po 2 < 17 mmHg were defined as hypoxic. At postmortem (<135 or >135 days), fetal hearts were collected, and cardiomyocytes were isolated and fixed. Proliferating cardiomyocytes were counted by immunohistochemistry of Ki67 protein. Cardiomyocytes were stained with methylene blue to visualize the nuclei, and the proportion of mononucleated cells and length and width of cardiomyocytes were measured. PR resulted in chronic fetal hypoxia, IUGR, and elevated plasma cortisol concentrations. Although there was no difference in relative heart weights between control and PR fetuses, there was an increase in the proportion of mononucleated cardiomyocytes in PR fetuses. Whereas mononucleated and binucleated cardiomyocytes were smaller, the relative size of cardiomyocytes when expressed relative to heart weight was larger in PR compared with control fetuses. The increase in the relative proportion of mononucleated cardiomyocytes and the relative sparing of the growth of individual cardiomyocytes in the growth-restricted fetus are adaptations that may have long-term consequences for heart development in postnatal life.
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A growth-restricted fetus has smaller coronary arteries, fewer but more immature cardiomyocytes, less elastin in the arteries, and fewer nephrons in the kidney.
“For example, a growth-restricted fetus has smaller coronary arteries (288), fewer but more immature cardiomyocytes (55,348,394), less elastin in the arteries (152, 362, 526), and fewer nephrons in the kidney (22,352).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [394]
Cites
WEIGHT IN INFANCY AND DEATH FROM ISCHAEMIC HEART DISEASE
Barker, D. J. P., Osmond, C., Winter, P. D., Margetts, B., & Simmonds, S. J. (1989) · The Lancet · doi:10.1016/s0140-6736(89)90710-1 · Cited by 3,574 · see citing works
Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming
Mcmillen, I. C., & Robinson, J. S. (2005) · Physiological Reviews · doi:10.1152/physrev.00053.2003 · Cited by 1,910 · see citing works
Self-citationCardiomyocyte DNA synthesis and binucleation during murine development
Soonpaa, M. H., Kim, K. K., Pajak, L., Franklin, M. T., & Field, L. J. (1996) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1996.271.5.h2183 · Cited by 718 · see citing works
Myocyte Death, Growth, and Regeneration in Cardiac Hypertrophy and Failure
Nadal‐Ginard, B., Kajstura, J., Leri, A., & Anversa, P. (2003) · Circulation Research · doi:10.1161/01.res.0000053618.86362.df · Cited by 501 · see citing works
Restricted fetal growth in sudden intrauterine unexplained death
Frøen, J. F., Gardosi, J. O., Thurmann, A., Francis, A. I., & Stray‐Pedersen, B. (2004) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1111/j.0001-6349.2004.00602.x · Cited by 345 · see citing works
Cerebral palsy and intrauterine growth in single births: European collaborative study
Jarvis, S. N., Glinianaia, S. V., Torrioli, M. G., Platt, M., Miceli, M., Jouk, P., Johnson, A., Hutton, J. L., Hemming, K., Hagberg, G., et al. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14466-2 · Cited by 321 · see citing works
Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts
Soonpaa, M. H., & Field, L. J. (1997) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1997.272.1.h220 · Cited by 308 · see citing works
Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy.
Clubb, F. J., & Bishop, S. P. (1984) · PubMed · Cited by 265 · see citing works
Fetal growth restriction: adaptations and consequences
McMillen, I. C., Adams, M. B., Ross, J. T., Coulter, C. L., Simonetta, G., Owens, J. A., Robinson, J. S., & Edwards, L. J. (2001) · Reproduction · doi:10.1530/rep.0.1220195 · Cited by 262 · see citing works
Self-citationEffect of Fetal Hypoxia on Heart Susceptibility to Ischemia and Reperfusion Injury in the Adult Rat
Guo-hu, L., Xiao, Y., Estrella, J. L., Ducsay, C. A., Gilbert, R. D., & Zhang, L. (2003) · Journal of the Society for Gynecologic Investigation · doi:10.1016/s1071-5576(03)00074-1 · Cited by 199 · see citing works
Cardiomyocytes structure, function and associated pathologies
Woodcock, E. A., & Matkovich, S. J. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.04.011 · Cited by 192 · see citing works
Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart
Bae, S., Xiao, Y., Guo-hu, L., Casiano, C. A., & Zhang, L. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00005.2003 · Cited by 184 · see citing works
Plasma Cortisol and Adrenocorticotropin in Appropriate and Small for Gestational Age Fetuses
Economides, D. L., Nicolaides, K. H., Linton, E. A., Perry, L., & Chard, T. (1988) · Fetal Diagnosis and Therapy · doi:10.1159/000263348 · Cited by 179 · see citing works
Effect of Intrauterine Growth Restriction on the Number of Cardiomyocytes in Rat Hearts
Corstius, H. B., Zimanyi, M. A., Maka, N., Herath, T., Thomas, W. G., van der Laarse, A., Wreford, N. G., & Black, M. J. (2005) · Pediatric Research · doi:10.1203/01.pdr.0000157726.65492.cd · Cited by 169 · see citing works
Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart
Jonker, S. S., Zhang, L., Louey, S., Giraud, G. D., Thornburg, K. L. R., & Faber, J. J. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00937.2006 · Cited by 160 · see citing works
Self-citationGrowth and maturation of cardiac myocytes in fetal sheep in the second half of gestation
Burrell, J. H., Boyn, A. M., Kumarasamy, V., Hsieh, A., Head, S. I., & Lumbers, E. R. (2003) · The Anatomical Record Part A Discoveries in Molecular Cellular and Evolutionary Biology · doi:10.1002/ar.a.10110 · Cited by 157 · see citing works
Whittle, W. L., Patel, F. A., Alfaidy, N., Holloway, A. C., Fraser, M., Gyomorey, S., Lye, S. J., Gibb, W., & Challis, J. R. G. (2001) · Biology of Reproduction · doi:10.1095/biolreprod64.4.1019 · Cited by 157 · see citing works
Very low birthweight boys at the age of 19
Ericson, A., & Kallen, B. (1998) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/fn.78.3.f171 · Cited by 154 · see citing works
STUDIES ON THE PLACENTA OF THE SHEEP ( OVIS ARIES L.)
Alexander, G. M. (1964) · Reproduction · doi:10.1530/jrf.0.0070289 · Cited by 150 · see citing works
STUDIES ON THE PLACENTA OF THE SHEEP ( OVIS ARIES L.)
Alexander, G. M. (1964) · Reproduction · doi:10.1530/jrf.0.0070307 · Cited by 143 · see citing works
Bubb, K. J., Cock, M. L., Black, M. J., Dodic, M., Boon, W., Parkington, H. C., Harding, R., & Tare, M. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.121160 · Cited by 139 · see citing works
Left and right ventricular myocardial morphometry in fetal, neonatal, and adult sheep
Smolich, J. J., WALKER, A. M., CAMPBELL, G. R., & Adamson, T. M. (1989) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1989.257.1.h1 · Cited by 137 · see citing works
Right ventricular systolic pressure load alters myocyte maturation in fetal sheep
Barbera, A. F., Giraud, G. D., Reller, M. D., Maylie, J., Morton, M. J., & Thornburg, K. L. R. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.4.r1157 · Cited by 135 · see citing works
Self-citationEdwards, L. J., Simonetta, G., Owens, J. A., Robinson, J. S., & McMillen, I. C. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.897ab.x · Cited by 131 · see citing works
Self-citationPhillips, I. D., Simonetta, G., Owens, J. A., Robinson, J. S., Clarke, I. J., & McMillen, I. C. (1996) · Pediatric Research · doi:10.1203/00006450-199612000-00014 · Cited by 131 · see citing works
Self-citationSundgren, N. C., Giraud, G. D., Schultz, J. M., Lasarev, M. R., Stork, P. A., & Thornburg, K. L. R. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00232.2003 · Cited by 131 · see citing works
Self-citationMetabolic and endocrine findings in appropriate and small for gestational age fetuses
Economides, D. L., Nicolaides, K. H., & Campbell, S. C. (1991) · Journal of Perinatal Medicine · doi:10.1515/jpme.1991.19.1-2.97 · Cited by 129 · see citing works
Owens, J. A., Kind, K. L., Carbone, F., Robinson, J. S., & Owens, P. C. (1994) · Journal of Endocrinology · doi:10.1677/joe.0.1400005 · Cited by 121 · see citing works
Changes in pituitary responses to synthetic ovine corticotrophin releasing factor in fetal sheep
Norman, L. J., Lye, S. J., Wlodek, M. E., & Challis, J. R. G. (1985) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y85-230 · Cited by 120 · see citing works
Louey, S., Jonker, S. S., Giraud, G. D., & Thornburg, K. L. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2006.122200 · Cited by 116 · see citing works
Self-citationCortisol Stimulates Cell Cycle Activity in the Cardiomyocyte of the Sheep Fetus
Giraud, G. D., Louey, S., Jonker, S. S., Schultz, J., & Thornburg, K. L. R. (2006) · Endocrinology · doi:10.1210/en.2006-0061 · Cited by 111 · see citing works
Self-citationFetal growth restriction: a workshop report
Cetin, I., Foidart, J., Miozzo, M. R., Raun, T., Jansson, T., Tsatsaris, V., Reik, W., Cross, J. C., Mouzon, S. H., Illsley, N. P., et al. (2004) · Placenta · doi:10.1016/j.placenta.2004.02.004 · Cited by 107 · see citing works
Danielson, L., McMillen, I. C., Dyer, J. L., & Morrison, J. L. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2004.080523 · Cited by 103 · see citing works
Self-citationAngiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes
Sundgren, N. C., Giraud, G. D., Stork, P. A., Maylie, J., & Thornburg, K. L. R. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.038778 · Cited by 102 · see citing works
Self-citationThorburn, G. D., & Harding, R. (1994) · Oxford University Press eBooks · Cited by 96 · see citing works
Leri, A., Barlucchi, L., Limana, F., Deptała, A., Darżynkiewicz, Z., Hintze, T. H., Kajstura, J., Nadal‐Ginard, B., & Anversa, P. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151013298 · Cited by 95 · see citing works
Impact of Placental Restriction on the Development of the Sympathoadrenal System
Simonetta, G., Rourke, A. K., Owens, J. A., Robinson, J. S., & McMillen, I. C. (1997) · Pediatric Research · doi:10.1203/00006450-199712000-00015 · Cited by 92 · see citing works
Self-citationEndl, E., & Gerdes, J. (2000) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(200003)182:3 · Cited by 89 · see citing works
The predominance of binucleation in isolated rat heart myocytes
KATZBERG, A. A., Farmer, B. B., & Harris, R. A. (1977) · American Journal of Anatomy · doi:10.1002/aja.1001490406 · Cited by 86 · see citing works
Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep
Lumbers, E. R., Boyce, A. C., Joulianos, G., Kumarasamy, V., Barner, E. W., Segar, J. L., & Burrell, J. H. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00556.2004 · Cited by 80 · see citing works
The prenatal environment and later cardiovascular disease
Louey, S., & Thornburg, K. L. R. (2005) · Early Human Development · doi:10.1016/j.earlhumdev.2005.07.001 · Cited by 76 · see citing works
Self-citationBirth Weight and Cardiac Structure in Children
Jiang, B., Godfrey, K. M., Martyn, C. N., & Gale, C. R. (2006) · Pediatrics · doi:10.1542/peds.2005-1325 · Cited by 72 · see citing works
Perinatal Myocardial DNA and Protein Changes in the Lamb: Effect of Cortisol in the Fetus
Rudolph, A. M., Roman, C., & Gournay, V. (1999) · Pediatric Research · doi:10.1203/00006450-199908000-00002 · Cited by 65 · see citing works
Jonker, S. S., Faber, J. J., Anderson, D. F., Thornburg, K. L. R., Louey, S., & Giraud, G. D. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00484.2006 · Cited by 59 · see citing works
Self-citationFetal behavioural state changes following maternal fluoxetine infusion in sheep
Morrison, J. L., Chien, C., Gruber, N., Rurak, D. W., & Riggs, W. K. (2001) · Developmental Brain Research · doi:10.1016/s0165-3806(01)00255-3 · Cited by 54 · see citing works
Self-citationHemodynamic alteration by fetal surgery accelerates myocyte proliferation in fetal guinea pig hearts
Saiki, Y., Konig, A., Waddell, J., et al. (1997) · Surgery · doi:10.1016/s0039-6060(97)90034-9 · Cited by 54 · see citing works
Morrison, J. L., Riggs, K. W., Chien, C., Gruber, N., McMillen, I. C., & Rurak, D. W. (2004) · Pediatric Research · doi:10.1203/01.pdr.0000128981.38670.28 · Cited by 41 · see citing works
Self-citationMortola, J. P., Xu, L., & Lauzon, A. (1990) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y90-242 · Cited by 38 · see citing works
Myocyte proliferation and ventricular remodeling
Leri, A., Kajstura, J., & Anversa, P. (2002) · Journal of Cardiac Failure · doi:10.1054/jcaf.2002.129269 · Cited by 36 · see citing works
Cerebral Palsy and Intrauterine Growth in Single Births: European Collaborative Study
Jarvis, S. N., Glinalanaia, S. V., Torrioli, M.-G., et al. (2004) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000119177.78378.b3 · Cited by 27 · see citing works
Myocardial DNA and cell number under the influence of cytostatics
Adler, C.-P., & Costabel, U. (1980) · Virchows Archiv B Cell Pathology Including Molecular Pathology · doi:10.1007/bf02889020 · Cited by 20 · see citing works
The mutual interaction of vasoconstriction and endothelial damage in stenotic arteries
Tulenko, T. N., Constantinescu, D., Kikuchi, T., Cox, R. H., & Santamore, W. P. (1989) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1989.257.4.1-a · Cited by 14 · see citing works
Swamy, R. S., & Embleton, N. D. (2006) · PEDIATRICS · doi:10.1542/peds.2005-2360 · Cited by 11 · see citing works
Warnes, K. E., Coulter, C. L., Robinson, J. S., & McMillen, I. C. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00621.x · Cited by 9 · see citing works
Self-citationMyocardial DNA and cell number under the influence of cytostatics
Costabel, U., & Adler, C.-P. (1980) · Virchows Archiv B Cell Pathology Including Molecular Pathology · doi:10.1007/bf02889021 · Cited by 9 · see citing works
Warnes, K. E. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.049437 · Cited by 9 · see citing works
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Self-citation
- Authors
- Morrison, J. L., Botting, K. J., Dyer, J. L., Williams, S. J., Thornburg, K. L., & McMillen, I. C.
- Affiliations
- The University of Adelaide (AU)
- University of South Australia (AU)
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2007-07
- Volume
- 293
- Issue
- 1
- Pages
- R306-R313
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- OpenAlex
- W2103433863
- Cited by
- 184
- References
- 56
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 9 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 10 · 2019: 7 · 2018: 17 · 2017: 13 · 2016: 8 · 2015: 11 · 2014: 9 · 2013: 13 · 2012: 11
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- fetal hypoxia, fetal growth restriction, heart development, cardiomyocyte proliferation, cardiomyocyte size, fetal sheep, cortisol
- MeSH terms
- Animals, Blood Gas Analysis, Female, Fetal Hypoxia, Fetal Growth Retardation, Fetus, Heart, Hydrocortisone, Hyperplasia, Male, Myocardium, Oxygen Consumption, Placenta, Pregnancy, Sex Characteristics, Sheep, Myocytes, Cardiac, Cell Size, Cell Proliferation
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