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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

Litter sizes, maternal, placental and fetal weights, and placental/fetal weight ratios.Controls (n = 17) and msFlt-1(1-3)-treated mice (n = 6) had a litter size consistent with the strain average published by the vendor (n = 11.5). The number of pups (13.8±0.4, p = 0.046) and living pups (13.6±0.45, p = 0.05) were higher in hsFlt-1-e15a-treated mice (n = 18) than in controls. The total weight of living pups (14.2±0.56 g, p = 0.04) and maternal weights (56.3±1.1 g, p = 0.04) were also higher in hsFlt-1-e15a-treated mice than in controls. Truncated msFlt-1(1-3)-treated mice did not differ in any parameters from the controls. Among hsFlt-1-e15a-treated mice, the total weights of living pups was higher in the Ad-RGD-CYP-hsFlt-1-e15a treated mice than in controls (15±0.48 g, p = 0.043). The number of pups (14.3±0.42, p = 0.047) and the number of living pups (14.1±0.46, p = 0.039) was higher in the Ad-RGD-CMV-hsFlt-1-e15a treated mice than in controls. Stars denote statistical significance.
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pone-0110867-g009: Litter sizes, maternal, placental and fetal weights, and placental/fetal weight ratios.Controls (n = 17) and msFlt-1(1-3)-treated mice (n = 6) had a litter size consistent with the strain average published by the vendor (n = 11.5). The number of pups (13.8±0.4, p = 0.046) and living pups (13.6±0.45, p = 0.05) were higher in hsFlt-1-e15a-treated mice (n = 18) than in controls. The total weight of living pups (14.2±0.56 g, p = 0.04) and maternal weights (56.3±1.1 g, p = 0.04) were also higher in hsFlt-1-e15a-treated mice than in controls. Truncated msFlt-1(1-3)-treated mice did not differ in any parameters from the controls. Among hsFlt-1-e15a-treated mice, the total weights of living pups was higher in the Ad-RGD-CYP-hsFlt-1-e15a treated mice than in controls (15±0.48 g, p = 0.043). The number of pups (14.3±0.42, p = 0.047) and the number of living pups (14.1±0.46, p = 0.039) was higher in the Ad-RGD-CMV-hsFlt-1-e15a treated mice than in controls. Stars denote statistical significance.

Mentions: Fetal survival rate, average fetal weights, placental weights, and placental/fetal weight ratios were not affected by either hsFlt-1-e15a or msFlt-1(1-3) treatments (Figure 9). Controls (n = 17) and msFlt-1(1-3)-treated mice (n = 6) had a litter size consistent with the average published by the vendor (n = 11.5). The number of pups (13.8±0.4, p = 0.046) and living pups (13.6±0.45, p = 0.05) were higher in hsFlt-1-e15a-treated mice (n = 18) than in controls. The total weight of living pups (14.2±0.56g, p = 0.04) and maternal weights (56.3±1.1g, p = 0.04) were also higher in hsFlt-1-e15a-treated mice than in controls. Mouse sFlt-1(1-3)-treated mice did not differ in any parameters from the controls. When analyzing the subgroups of hsFlt-1-e15a-treated mice, the total weights of living pups was higher in the Ad-RGD-CYP-hsFlt-1-e15a treatment group than in controls (15±0.48g, p = 0.043). The number of pups (14.3±0.42, p = 0.047) and the number of living pups (14.1±0.46, p = 0.039) was higher in the Ad-RGD-CMV-hsFlt-1-e15a-treated mice than in controls.


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)

Litter sizes, maternal, placental and fetal weights, and placental/fetal weight ratios.Controls (n = 17) and msFlt-1(1-3)-treated mice (n = 6) had a litter size consistent with the strain average published by the vendor (n = 11.5). The number of pups (13.8±0.4, p = 0.046) and living pups (13.6±0.45, p = 0.05) were higher in hsFlt-1-e15a-treated mice (n = 18) than in controls. The total weight of living pups (14.2±0.56 g, p = 0.04) and maternal weights (56.3±1.1 g, p = 0.04) were also higher in hsFlt-1-e15a-treated mice than in controls. Truncated msFlt-1(1-3)-treated mice did not differ in any parameters from the controls. Among hsFlt-1-e15a-treated mice, the total weights of living pups was higher in the Ad-RGD-CYP-hsFlt-1-e15a treated mice than in controls (15±0.48 g, p = 0.043). The number of pups (14.3±0.42, p = 0.047) and the number of living pups (14.1±0.46, p = 0.039) was higher in the Ad-RGD-CMV-hsFlt-1-e15a treated mice than in controls. Stars denote statistical significance.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4230935&req=5

pone-0110867-g009: Litter sizes, maternal, placental and fetal weights, and placental/fetal weight ratios.Controls (n = 17) and msFlt-1(1-3)-treated mice (n = 6) had a litter size consistent with the strain average published by the vendor (n = 11.5). The number of pups (13.8±0.4, p = 0.046) and living pups (13.6±0.45, p = 0.05) were higher in hsFlt-1-e15a-treated mice (n = 18) than in controls. The total weight of living pups (14.2±0.56 g, p = 0.04) and maternal weights (56.3±1.1 g, p = 0.04) were also higher in hsFlt-1-e15a-treated mice than in controls. Truncated msFlt-1(1-3)-treated mice did not differ in any parameters from the controls. Among hsFlt-1-e15a-treated mice, the total weights of living pups was higher in the Ad-RGD-CYP-hsFlt-1-e15a treated mice than in controls (15±0.48 g, p = 0.043). The number of pups (14.3±0.42, p = 0.047) and the number of living pups (14.1±0.46, p = 0.039) was higher in the Ad-RGD-CMV-hsFlt-1-e15a treated mice than in controls. Stars denote statistical significance.
Mentions: Fetal survival rate, average fetal weights, placental weights, and placental/fetal weight ratios were not affected by either hsFlt-1-e15a or msFlt-1(1-3) treatments (Figure 9). Controls (n = 17) and msFlt-1(1-3)-treated mice (n = 6) had a litter size consistent with the average published by the vendor (n = 11.5). The number of pups (13.8±0.4, p = 0.046) and living pups (13.6±0.45, p = 0.05) were higher in hsFlt-1-e15a-treated mice (n = 18) than in controls. The total weight of living pups (14.2±0.56g, p = 0.04) and maternal weights (56.3±1.1g, p = 0.04) were also higher in hsFlt-1-e15a-treated mice than in controls. Mouse sFlt-1(1-3)-treated mice did not differ in any parameters from the controls. When analyzing the subgroups of hsFlt-1-e15a-treated mice, the total weights of living pups was higher in the Ad-RGD-CYP-hsFlt-1-e15a treatment group than in controls (15±0.48g, p = 0.043). The number of pups (14.3±0.42, p = 0.047) and the number of living pups (14.1±0.46, p = 0.039) was higher in the Ad-RGD-CMV-hsFlt-1-e15a-treated mice than in controls.

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