In vivo experiments reveal the good, the bad and the ugly faces of sFlt-1 in pregnancy.
OBJECTIVE
Soluble fms-like tyrosine kinase (sFlt)-1-e15a, a primate-specific sFlt-1-isoform most abundant in the human placenta in preeclampsia, can induce preeclampsia in mice. This study compared the effects of full-length human (h)sFlt-1-e15a with those of truncated mouse (m)sFlt-1(1-3) used in previous preeclampsia studies on pregnancy outcome and clinical symptoms in preeclampsia.


METHODS
Mice were injected with adenoviruses or fiber-mutant adenoviruses overexpressing hsFlt-1-e15a, msFlt-1(1-3) or control GFP under the CMV or CYP19A1 promoters on gestational day 8 (GD8) and GD11. Placentas and pups were delivered by cesarean section, and dams were monitored postpartum. Blood pressure was telemetrically recorded. Urine samples were collected with cystocentesis and examined for albumin/creatinine ratios. Tissue specimens were evaluated for transgene as well as endogenous mFlt-1 and msFlt-1-i13 expression. H&E-, Jones- and PAS-stained kidney sections were histopathologically examined. Placental GFP expression and aortic ring assays were investigated with confocal microscopy.


RESULTS
Mean arterial blood pressure (MAP) was elevated before delivery in hsFlt-1-e15a-treated mice compared to controls (GD18: ΔMAP = 7.8 mmHg, p = 0.009), while ΔMAP was 12.8 mmHg (GD18, p = 0.005) in msFlt-1(1-3)-treated mice. Urine albumin/creatinine ratio was higher in hsFlt-1-e15a-treated mice than in controls (GD18, p = 0.04; PPD8, p = 0.03), and msFlt-1(1-3)-treated mice had marked proteinuria postpartum (PPD8, p = 4 × 10(-5)). Focal glomerular changes were detected in hsFlt-1-e15a and msFlt-1(1-3)-treated mice. Aortic ring microvessel outgrowth was decreased in hsFlt-1-e15a (p = 0.007) and msFlt-1(1-3)-treated (p = 0.02) mice. Full-length msFlt-1-i13 expression was unique for the placenta. In hsFlt-1-e15a-treated mice, the number of pups (p = 0.046), total weight of living pups (p = 0.04) and maternal weights (p = 0.04) were higher than in controls. These differences were not observed in truncated msFlt-1(1-3)-treated mice.


CONCLUSIONS
Truncated msFlt-1(1-3) simulated the preeclampsia-promoting effects of full-length hsFlt-1. MsFlt-1(1-3) had strong effect on maternal endothelium but not on placentas and embryos. In contrast, hsFlt-1-e15a induced preeclampsia-like symptoms; however, it also increased litter size. In accord with the predominant placental expression of hsFlt-1-e15a and msFlt-1-i13, full-length sFlt-1 may have a role in the regulation of embryonic development. These observations point to the difference in the biological effects of full-length and truncated sFlt-1 and the changes in the effect of full-length sFlt-1 during pregnancy, and may have important implications in the management of preeclampsia.
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, MD, and Detroit, MI, United States of America.
Gabor
G
Szalai
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, MD, and Detroit, MI, United States of America.
Yi
Y
Xu
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, MD, and Detroit, MI, United States of America.
Roberto
R
Romero
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, MD, and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States of America.
Tinnakorn
T
Chaiworapongsa
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, MD, and Detroit, MI, United States of America.
Zhonghui
Z
Xu
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, MD, and Detroit, MI, United States of America.
Po Jen
PJ
Chiang
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, MD, and Detroit, MI, United States of America.
Hyunyoung
H
Ahn
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, MD, and Detroit, MI, United States of America.
Birgitta
B
Sundell
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, MD, and Detroit, MI, United States of America.
Olesya
O
Plazyo
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, MD, and Detroit, MI, United States of America.
Yang
Y
Jiang
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, MD, and Detroit, MI, United States of America; Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States of America.
Mary
M
Olive
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, MD, and Detroit, MI, United States of America.
Bing
B
Wang
Department of Pathology, Wayne State University School of Medicine, Detroit, MI, United States of America.
Suzanne M
SM
Jacques
Department of Pathology, Wayne State University School of Medicine, Detroit, MI, United States of America.
Faisal
F
Qureshi
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, MD, and Detroit, MI, United States of America; Department of Computer Science, Wayne State University, Detroit, MI, United States of America; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, United States of America.
Adi L
AL
Tarca
Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Offer
O
Erez
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, MD, and Detroit, MI, United States of America.
Zhong
Z
Dong
Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary.
Zoltan
Z
Papp
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, MD, and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States of America.
Sonia S
SS
Hassan
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, MD, and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States of America.
Edgar
E
Hernandez-Andrade
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, MD, and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 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.
Nandor Gabor
NG
Than
D000256:Adenoviridae / Q000235:genetics; D000419:Albuminuria / Q000652:urine; D000818:Animals; D062186:Arterial Pressure / Q000502:physiology; D003404:Creatinine / Q000652:urine; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008098:Litter Size / Q000235:genetics / Q000502:physiology; D051379:Mice; D055806:Microvessels / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010920:Placenta; D011225:Pre-Eclampsia / Q000235:genetics* / Q000503:physiopathology*; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics*; D011257:Pregnancy Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000652:urine; D019076:Transgenes / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
D010455:Peptides; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D049452:Green Fluorescent Proteins; D003404:Creatinine; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1