Abstract
ObjectiveSoluble 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.MethodsMice 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.ResultsMean 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.ConclusionsTruncated 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.
Highlights
Human pregnancy is a unique state of maternal-fetal immune tolerance [1,2,3,4,5,6,7,8,9,10,11,12,13], and it was thought to be predominantly an antiinflammatory state [14]
HsFlt-1-e15a has predominant placental expression among other tissues, and it is the most abundant placenta-expressed Soluble fms-like tyrosine kinase (sFlt)-1 variant in healthy pregnancies and those affected by preeclampsia [70,71,74,118,119]. These findings suggest that hsFlt-1-e15a may have important functions in normal pregnancy; its overexpression may promote the development of preeclampsia
The development of various transgene delivery systems In order to compare the effects of the full-length hsFlt-1-e15a with that of the truncated msFlt-1(1-3), viral constructs containing these two transgenes were constructed (Figure 2A)
Summary
Human pregnancy is a unique state of maternal-fetal immune tolerance [1,2,3,4,5,6,7,8,9,10,11,12,13], and it was thought to be predominantly an antiinflammatory state [14]. Pro-inflammatory mechanisms play key roles in trophoblast invasion and remodeling of maternal spiral arteries, resulting in the adequate blood supply for the placental-fetal unit [15,16]. This period is followed by an anti-inflammatory state characterized by accelerated fetal growth and development. At the end of pregnancy, proinflammatory pathways are key in spontaneous parturition, promoting the activation of the decidua and myometrium, cervical ripening, uterine contractions, and the delivery of the fetus and placenta [17,18,19,20,21,22,23,24]. The early activation of local proinflammatory mechanisms involved in parturition as well as systemic inflammation in the mother are central to the development of most obstetrical syndromes (e.g. preterm birth, preeclampsia or unexplained fetal demise) [20,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]
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