Increased arterial stiffness and extracellular matrix reorganization in intrauterine growth–restricted fetal sheep
Open accessAbstract
Background Fetal intrauterine growth restriction (IUGR) results in increased placental resistance to blood flow, fetal hypertension, and increased pulsatility stresses shown to lead to vascular remodeling. We tested our hypothesis that IUGR causes decreased compliance in the carotid and umbilical arteries due to altered extracellular matrix (ECM) composition and structure.Methods A sheep model of placental insufficiency-induced IUGR (PI-IUGR) was created by exposure of the pregnant ewe to elevated ambient temperatures. Umbilical and carotid arteries from near-term fetuses were tested with pressure-diameter measurements to compare passive compliance in control and PI-IUGR tissues. ECM composition was measured via biochemical assay, and the organization was determined by using histology and second-harmonic generation imaging.Results We found that PI-IUGR increased arterial stiffness with increased collagen engagement, or transition stretch. PI-IUGR carotid arteries exhibited increased collagen and elastin quantity, and PI-IUGR umbilical arteries exhibited increased sulfated glycosaminoglycans. Histomorphology showed altered collagen-to-elastin ratios with altered cellular proliferation. Increased stiffness indicates altered collagen-to-elastin ratios with less elastin contribution leading to increased collagen engagement.Conclusion Because vessel stiffness is a significant predictor in the development of hypertension, disrupted ECM deposition in IUGR provides a potential link between IUGR and adult hypertension.
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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 [152]
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Nilsson, P. M. (2015) · Springer eBooks · doi:10.1007/978-3-319-14556-3_14
Arenas, G. A., Navarrete, Á., González, J. M., Utrera, A., García-Herrera, C., & Krause, B. J. (2026) · PNAS Nexus · doi:10.1093/pnasnexus/pgag158
Arenas, G. A., Herrera, E. A., Krause, B. J., Giussani, D. A., Julian, C. G., MOORE, L. G., & Lorca, R. A. (2026) · Physiological Reviews · doi:10.1152/physrev.00003.2026
Biswas, A., Mondal, S., Mathew, S. J., & Maiti, T. K. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.22.746430
- Authors
- Dodson, R. B., Rozance, P. J., Fleenor, B. S., Petrash, C. C., Shoemaker, L. G., Hunter, K. S., & Ferguson, V. L.
- Affiliations
- University of Colorado Boulder (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Ferguson, Virginia L.
- ORCID
- Venue
- Pediatric Research
- Published
- 2012-11-15
- Volume
- 73
- Issue
- 2
- Pages
- 147-154
- ISSN
- 0031-3998 (ISSN-L)
- 1530-0447
- PMC
- PMC3742323
- OpenAlex
- W2071376278
- Cited by
- 62
- References
- 38
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 4 · 2016: 3 · 2015: 10 · 2014: 3 · 2013: 5
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pediatric Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (1K08HD060688-1)
- National Institutes of Health (4r01hl114887-05)
- National Heart, Lung, and Blood Institute (K25HL094749, R01 HL-114887)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088139)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD060688)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Physical Sciences › Engineering › Biomedical Engineering › Elasticity and Material Modeling
- Keywords
- fetal growth restriction, arterial stiffness, extracellular matrix, vascular remodeling, placental insufficiency, carotid artery, umbilical artery, elastin, glycosaminoglycans, fetal hypertension, fetal sheep model, vascular compliance
- MeSH terms
- Animals, Carotid Arteries, Collagen, Compliance, Disease Models, Animal, Elastin, Extracellular Matrix, Female, Fetal Growth Retardation, Gestational Age, Glycosaminoglycans, Hypertension, Male, Pregnancy, Sheep, Umbilical Arteries, Cell Proliferation, Vascular Stiffness
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