PMID- 25860260
OWN - NLM
STAT- MEDLINE
DCOM- 20160425
LR  - 20231111
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 4
DP  - 2015
TI  - Full-length human placental sFlt-1-e15a isoform induces distinct maternal 
      phenotypes of preeclampsia in mice.
PG  - e0119547
LID - 10.1371/journal.pone.0119547 [doi]
LID - e0119547
AB  - 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 mug/mg vs. 19.3 +/- 5.6 mug/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.
FAU - Szalai, Gabor
AU  - Szalai G
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Romero, Roberto
AU  - Romero R
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Chaiworapongsa, Tinnakorn
AU  - Chaiworapongsa T
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America; Department of Obstetrics and Gynecology, Wayne State University School 
      of Medicine, Detroit, Michigan, United States of America.
FAU - Xu, Yi
AU  - Xu Y
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Wang, Bing
AU  - Wang B
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Ahn, Hyunyoung
AU  - Ahn H
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Xu, Zhonghui
AU  - Xu Z
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Chiang, Po Jen
AU  - Chiang PJ
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Sundell, Birgitta
AU  - Sundell B
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Wang, Rona
AU  - Wang R
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Jiang, Yang
AU  - Jiang Y
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Plazyo, Olesya
AU  - Plazyo O
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Olive, Mary
AU  - Olive M
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America; Department of Pharmacology, Wayne State University School of Medicine, 
      Detroit, Michigan, United States of America.
FAU - Tarca, Adi L
AU  - Tarca AL
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America; Department of Computer Science, Wayne State University, Detroit, 
      Michigan, United States of America; Center for Molecular Medicine and Genetics, 
      Wayne State University School of Medicine, Detroit, Michigan, United States of 
      America.
FAU - Dong, Zhong
AU  - Dong Z
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America.
FAU - Qureshi, Faisal
AU  - Qureshi F
AD  - Department of Pathology, Wayne State University School of Medicine, Detroit, 
      Michigan, United States of America.
FAU - Papp, Zoltan
AU  - Papp Z
AD  - Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, 
      Budapest, Hungary.
FAU - Hassan, Sonia S
AU  - Hassan SS
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America; Department of Obstetrics and Gynecology, Wayne State University School 
      of Medicine, Detroit, Michigan, United States of America.
FAU - Hernandez-Andrade, Edgar
AU  - Hernandez-Andrade E
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America; Department of Obstetrics and Gynecology, Wayne State University School 
      of Medicine, Detroit, Michigan, United States of America.
FAU - Than, Nandor Gabor
AU  - Than NG
AD  - Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, National Institutes of Health, Department of Health 
      and Human Services, Bethesda, Maryland, and Detroit, Michigan, United States of 
      America; Department of Obstetrics and Gynecology, Wayne State University School 
      of Medicine, Detroit, Michigan, United States of America; Maternity Private 
      Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary; 
      Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy 
      of Sciences, Budapest, Hungary; First Department of Pathology and Experimental 
      Cancer Research, Semmelweis University, Budapest, Hungary.
LA  - eng
GR  - HHSN275201300006C/PHS HHS/United States
GR  - P30CA22453/CA/NCI NIH HHS/United States
GR  - Intramural NIH HHS/United States
GR  - HHSN275201300006C/HD/NICHD NIH HHS/United States
GR  - P30 CA022453/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150410
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.10.1 (FLT1 protein, human)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Blood Pressure
MH  - Blood Pressure Monitors
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Profiling
MH  - Gestational Age
MH  - Green Fluorescent Proteins/genetics
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Sequence Data
MH  - Phenotype
MH  - Placenta/diagnostic imaging/pathology/physiopathology
MH  - Pre-Eclampsia/*etiology/pathology/physiopathology
MH  - Pregnancy
MH  - Protein Isoforms/administration & dosage/genetics/physiology
MH  - RNA, Messenger/genetics/metabolism
MH  - Recombinant Proteins/administration & dosage/genetics
MH  - Sequence Homology, Amino Acid
MH  - Species Specificity
MH  - Telemetry
MH  - Ultrasonography
MH  - Vascular Endothelial Growth Factor Receptor-1/administration & 
      dosage/genetics/*physiology
PMC - PMC4393117
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/04/11 06:00
MHDA- 2016/04/26 06:00
PMCR- 2015/04/10
CRDT- 2015/04/11 06:00
PHST- 2014/05/20 00:00 [received]
PHST- 2015/01/30 00:00 [accepted]
PHST- 2015/04/11 06:00 [entrez]
PHST- 2015/04/11 06:00 [pubmed]
PHST- 2016/04/26 06:00 [medline]
PHST- 2015/04/10 00:00 [pmc-release]
AID - PONE-D-14-22488 [pii]
AID - 10.1371/journal.pone.0119547 [doi]
PST - epublish
SO  - PLoS One. 2015 Apr 10;10(4):e0119547. doi: 10.1371/journal.pone.0119547. 
      eCollection 2015.