title: Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice.
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.
authors: 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.
authors: Gabor
authors: G
authors: Szalai
authors: 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.
authors: Roberto
authors: R
authors: Romero
authors: 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.
authors: Tinnakorn
authors: T
authors: Chaiworapongsa
authors: 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.
authors: Yi
authors: Y
authors: Xu
authors: 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.
authors: Bing
authors: B
authors: Wang
authors: 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.
authors: Hyunyoung
authors: H
authors: Ahn
authors: 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.
authors: Zhonghui
authors: Z
authors: Xu
authors: 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.
authors: Po Jen
authors: PJ
authors: Chiang
authors: 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.
authors: Birgitta
authors: B
authors: Sundell
authors: 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.
authors: Rona
authors: R
authors: Wang
authors: 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.
authors: Yang
authors: Y
authors: Jiang
authors: 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.
authors: Olesya
authors: O
authors: Plazyo
authors: 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.
authors: Mary
authors: M
authors: Olive
authors: 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.
authors: Adi L
authors: AL
authors: Tarca
authors: 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.
authors: Zhong
authors: Z
authors: Dong
authors: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors: Faisal
authors: F
authors: Qureshi
authors: Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary.
authors: Zoltan
authors: Z
authors: Papp
authors: 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.
authors: Sonia S
authors: SS
authors: Hassan
authors: 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.
authors: Edgar
authors: E
authors: Hernandez-Andrade
authors: 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.
authors: Nandor Gabor
authors: NG
authors: Than
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure; D015924:Blood Pressure Monitors; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005865:Gestational Age; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype; D010920:Placenta / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D011225:Pre-Eclampsia / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D020033:Protein Isoforms / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013686:Telemetry; D014463:Ultrasonography; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1