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In vivo experiments reveal the good, the bad and the ugly faces of sFlt-1 in pregnancy.

Szalai G, Xu Y, Romero R, Chaiworapongsa T, Xu Z, Chiang PJ, Ahn H, Sundell B, Plazyo O, Jiang Y, Olive M, Wang B, Jacques SM, Qureshi F, Tarca AL, Erez O, Dong Z, Papp Z, Hassan SS, Hernandez-Andrade E, Than NG - PLoS ONE (2014)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Functional evaluation of the kidneys.(A) Chart depicts albumin/creatinine ratios (in log scale) in urine specimens from mice in the GFP, msFlt-1(1-3) and hsFlt-1-e15a-treated groups. Mean urine albumin/creatinine ratios were higher in hsFlt-1-e15a-treated mice (GD18, p = 0.04 and PPD8, p = 0.03) and msFlt-1(1-3)-treated mice (PPD8, p = 4×10−5) than in controls. Proteinuria was extremely high in the mouse overexpressing msFlt-1(1-3) with chronic hypertension. (B) Subgroup analysis showed that hsFlt-1-e15a expressed under the CMV promoter in the adenovirus led to significant increase in albumin/creatinine ratio on PPD8 (p = 0.003); hsFlt-1-e15a expressed under the CMV promoter in the fiber-mutant adenovirus led to significant increase in albumin/creatinine ratio on GD18 (p = 0.04); while hsFlt-1-e15a expressed under the CYP promoter in the fiber-mutant adenovirus led to a marginally significant increase in albumin/creatinine ratio on GD18 (p = 0.056) and a significant increase on PPD8 (p = 0.04).
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pone-0110867-g007: Functional evaluation of the kidneys.(A) Chart depicts albumin/creatinine ratios (in log scale) in urine specimens from mice in the GFP, msFlt-1(1-3) and hsFlt-1-e15a-treated groups. Mean urine albumin/creatinine ratios were higher in hsFlt-1-e15a-treated mice (GD18, p = 0.04 and PPD8, p = 0.03) and msFlt-1(1-3)-treated mice (PPD8, p = 4×10−5) than in controls. Proteinuria was extremely high in the mouse overexpressing msFlt-1(1-3) with chronic hypertension. (B) Subgroup analysis showed that hsFlt-1-e15a expressed under the CMV promoter in the adenovirus led to significant increase in albumin/creatinine ratio on PPD8 (p = 0.003); hsFlt-1-e15a expressed under the CMV promoter in the fiber-mutant adenovirus led to significant increase in albumin/creatinine ratio on GD18 (p = 0.04); while hsFlt-1-e15a expressed under the CYP promoter in the fiber-mutant adenovirus led to a marginally significant increase in albumin/creatinine ratio on GD18 (p = 0.056) and a significant increase on PPD8 (p = 0.04).

Mentions: For functional evidence of kidney damage, we also determined albumin/creatinine ratios in urine samples obtained serially during pregnancy. As Figure 7A shows, mean urine albumin/creatinine ratios were higher in hsFlt-1-e15a treated mice (GD18, 1.9-fold, p = 0.04 and PPD8, 1.7-fold, p = 0.03) than in controls. The albumin/creatinine ratio was markedly elevated in msFlt-1(1-3)-treated mice in the postpartum period (17-fold, p = 4×10−5). The dam in the msFlt-1(1-3)-treatment group with the constantly increasing blood pressure had extreme proteinuria with albumin/creatinine ratios of 3,070 µg/mg on GD18 and 15,401 µg/mg on PPD8.


In vivo experiments reveal the good, the bad and the ugly faces of sFlt-1 in pregnancy.

Szalai G, Xu Y, Romero R, Chaiworapongsa T, Xu Z, Chiang PJ, Ahn H, Sundell B, Plazyo O, Jiang Y, Olive M, Wang B, Jacques SM, Qureshi F, Tarca AL, Erez O, Dong Z, Papp Z, Hassan SS, Hernandez-Andrade E, Than NG - PLoS ONE (2014)

Functional evaluation of the kidneys.(A) Chart depicts albumin/creatinine ratios (in log scale) in urine specimens from mice in the GFP, msFlt-1(1-3) and hsFlt-1-e15a-treated groups. Mean urine albumin/creatinine ratios were higher in hsFlt-1-e15a-treated mice (GD18, p = 0.04 and PPD8, p = 0.03) and msFlt-1(1-3)-treated mice (PPD8, p = 4×10−5) than in controls. Proteinuria was extremely high in the mouse overexpressing msFlt-1(1-3) with chronic hypertension. (B) Subgroup analysis showed that hsFlt-1-e15a expressed under the CMV promoter in the adenovirus led to significant increase in albumin/creatinine ratio on PPD8 (p = 0.003); hsFlt-1-e15a expressed under the CMV promoter in the fiber-mutant adenovirus led to significant increase in albumin/creatinine ratio on GD18 (p = 0.04); while hsFlt-1-e15a expressed under the CYP promoter in the fiber-mutant adenovirus led to a marginally significant increase in albumin/creatinine ratio on GD18 (p = 0.056) and a significant increase on PPD8 (p = 0.04).
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Related In: Results  -  Collection

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pone-0110867-g007: Functional evaluation of the kidneys.(A) Chart depicts albumin/creatinine ratios (in log scale) in urine specimens from mice in the GFP, msFlt-1(1-3) and hsFlt-1-e15a-treated groups. Mean urine albumin/creatinine ratios were higher in hsFlt-1-e15a-treated mice (GD18, p = 0.04 and PPD8, p = 0.03) and msFlt-1(1-3)-treated mice (PPD8, p = 4×10−5) than in controls. Proteinuria was extremely high in the mouse overexpressing msFlt-1(1-3) with chronic hypertension. (B) Subgroup analysis showed that hsFlt-1-e15a expressed under the CMV promoter in the adenovirus led to significant increase in albumin/creatinine ratio on PPD8 (p = 0.003); hsFlt-1-e15a expressed under the CMV promoter in the fiber-mutant adenovirus led to significant increase in albumin/creatinine ratio on GD18 (p = 0.04); while hsFlt-1-e15a expressed under the CYP promoter in the fiber-mutant adenovirus led to a marginally significant increase in albumin/creatinine ratio on GD18 (p = 0.056) and a significant increase on PPD8 (p = 0.04).
Mentions: For functional evidence of kidney damage, we also determined albumin/creatinine ratios in urine samples obtained serially during pregnancy. As Figure 7A shows, mean urine albumin/creatinine ratios were higher in hsFlt-1-e15a treated mice (GD18, 1.9-fold, p = 0.04 and PPD8, 1.7-fold, p = 0.03) than in controls. The albumin/creatinine ratio was markedly elevated in msFlt-1(1-3)-treated mice in the postpartum period (17-fold, p = 4×10−5). The dam in the msFlt-1(1-3)-treatment group with the constantly increasing blood pressure had extreme proteinuria with albumin/creatinine ratios of 3,070 µg/mg on GD18 and 15,401 µg/mg on PPD8.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus