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Full-Length Human Placental sFlt-1-e15a Isoform Induces Distinct Maternal Phenotypes of Preeclampsia in Mice
Open accessAbstract
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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From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [141]
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Metadata
- 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
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-04-10
- Volume
- 10
- Issue
- 4
- Pages
- e0119547
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4393117
- 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
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- 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 › Clinical Neurology › 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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