Cited by 46Pregnancy and preeclampsia studiesNeurological Complications and SyndromesReproductive System and Pregnancy

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

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Szalai, Gabor, Romero, Roberto, Chaiworapongsa, Tinnakorn, Xu, Yi, Wang, Bing, Ahn, Hyunyoung, Xu, Zhonghui, Chiang, Po Jen +12 more·2015·PLoS ONE

Abstract

OBJECTIVE: Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring. METHODS: Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia. RESULTS: Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3 ± 51.7 μg/mg vs. 19.3 ± 5.6 μg/mg, p = 4.4 x 10(-2); GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2 x 10(-2)). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR). CONCLUSIONS: A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the in vivo pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.

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  1. [209]National Research Council of the National Academies: Guide for the Care and Use of Laboratory Animals. Washington, DC: The National Academies Press 2011.
  2. [234]HD-X11 Device Surgical Manual St.Paul: Data Science International; 2011 pp. 32.

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Authors
Szalai, G., Romero, R., Chaiworapongsa, T., Xu, Y., Wang, B., Ahn, H., Xu, Z., Chiang, P. J., Sundell, B., Wang, R., Jiang, Y., Plazyo, O., Olive, M., Tarca, A. L., Dong, Z., Qureshi, F., Papp, Z., Hassan, S. S., Hernandez-Andrade, E., & Than, N. G.
Affiliations
  • National Institutes of Health (US)
  • Wayne State University (US)
Corresponding author
Romero, Roberto
Venue
PLoS ONE
Published
2015-04-10
Volume
10
Issue
4
Pages
e0119547
ISSN
1932-6203 (ISSN-L)
OpenAlex
W1967129767
Cited by
46
References
292
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 4 · 2014: 2
FWCI
4.55
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Semmelweis University Repository (Semmelweis University) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services (HHSN275201300006C)
  • Wayne State University (HHSN275201300006C)
  • Barbara Ann Karmanos Cancer Institute
  • National Institutes of Health (Contract No. HHSN275201300006C, HHSN 275201300006C)
  • U.S. Public Health Service (HHSN275201300006C)
  • National Cancer Institute (P30CA 22453, P30CA022453)
  • National Institute of Child Health and Human Development (HHSN275201300006C, Contract No. HHSN275201300006C)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275201300006C, Contract No. HHSN275201300006C.)
  • NHLBI Division of Intramural Research
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
Keywords
preeclampsia, soluble fms-like tyrosine kinase-1, anti-angiogenic therapy, maternal hypertension, albuminuria, glomerular changes, postpartum monitoring, endothelial dysfunction, aortic ring assay
MeSH terms
Amino Acid Sequence, Animals, Blood Pressure, Disease Models, Animal, Female, Gestational Age, Humans, Mice, Transgenic, Molecular Sequence Data, Phenotype, Placenta, Pre-Eclampsia, Pregnancy, Recombinant Proteins, RNA, Messenger, Species Specificity, Telemetry, Ultrasonography, Blood Pressure Monitors, Sequence Homology, Amino Acid, Protein Isoforms, Gene Expression Profiling, Vascular Endothelial Growth Factor Receptor-1, Green Fluorescent Proteins, Mice

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