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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

Profiling of mFlt-1 and msFlt-1-i13 expression.(A) Boxplots show the endogenous expression profile of the mouse transmembrane Flt-1 mRNA in placentas harvested on gestational day (GD) 18 and in five tissues harvested on postpartum day (PPD) 8. Endogenous Flt-1 mRNA expression was highest in the placenta in both the non-treated (saline) and the msFlt-1(1-3)-treated mice. (B) Boxplots show the endogenous expression profile of the mouse sFlt-1-i13 mRNA in placentas harvested on GD18 and in five tissues harvested on PPD8. Endogenous msFlt-1-i13 mRNA expression was restricted to the placenta in control animals, and transgenic msFlt-1(1-3) expression was detected in the placenta and the liver.
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pone-0110867-g003: Profiling of mFlt-1 and msFlt-1-i13 expression.(A) Boxplots show the endogenous expression profile of the mouse transmembrane Flt-1 mRNA in placentas harvested on gestational day (GD) 18 and in five tissues harvested on postpartum day (PPD) 8. Endogenous Flt-1 mRNA expression was highest in the placenta in both the non-treated (saline) and the msFlt-1(1-3)-treated mice. (B) Boxplots show the endogenous expression profile of the mouse sFlt-1-i13 mRNA in placentas harvested on GD18 and in five tissues harvested on PPD8. Endogenous msFlt-1-i13 mRNA expression was restricted to the placenta in control animals, and transgenic msFlt-1(1-3) expression was detected in the placenta and the liver.

Mentions: First, we aimed to detect the expression profile and levels of msFlt-1 in mice that had not received any viral injection. Total RNAs were isolated from placentas harvested on GD18, as well as from brain, kidney, liver, spleen, and uterine tissues harvested on PPD8. The expression of the endogenous transmembrane mFlt-1 mRNA was the highest in the placentas among the six tissues of mice that had not received virus injection (Figure 3A); msFlt-1-i13 mRNA expression was solely detected in the placentas of these non-treated animals (Figure 3B). Of note, the placental expression of msFlt-1-i13 mRNA was the highest among all tissues, genes and transcripts investigated in this study (Figure 3B). When we injected mice with the viral construct overexpressing the truncated msFlt-1(1-3), we observed the appearance of msFlt-1 mRNA expression in the liver (Figure 3B). The placental transcript levels of msFlt-1-i13 mRNA were not evidently increased in animals injected with the viral construct overexpressing truncated msFlt-1(1-3) compared to saline-treated mice, suggesting that the endogenous placental msFlt-1-i13 mRNA expression is higher than that of the transgene expressed msFlt-1(1-3) mRNA (Figure 3B).


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)

Profiling of mFlt-1 and msFlt-1-i13 expression.(A) Boxplots show the endogenous expression profile of the mouse transmembrane Flt-1 mRNA in placentas harvested on gestational day (GD) 18 and in five tissues harvested on postpartum day (PPD) 8. Endogenous Flt-1 mRNA expression was highest in the placenta in both the non-treated (saline) and the msFlt-1(1-3)-treated mice. (B) Boxplots show the endogenous expression profile of the mouse sFlt-1-i13 mRNA in placentas harvested on GD18 and in five tissues harvested on PPD8. Endogenous msFlt-1-i13 mRNA expression was restricted to the placenta in control animals, and transgenic msFlt-1(1-3) expression was detected in the placenta and the liver.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110867-g003: Profiling of mFlt-1 and msFlt-1-i13 expression.(A) Boxplots show the endogenous expression profile of the mouse transmembrane Flt-1 mRNA in placentas harvested on gestational day (GD) 18 and in five tissues harvested on postpartum day (PPD) 8. Endogenous Flt-1 mRNA expression was highest in the placenta in both the non-treated (saline) and the msFlt-1(1-3)-treated mice. (B) Boxplots show the endogenous expression profile of the mouse sFlt-1-i13 mRNA in placentas harvested on GD18 and in five tissues harvested on PPD8. Endogenous msFlt-1-i13 mRNA expression was restricted to the placenta in control animals, and transgenic msFlt-1(1-3) expression was detected in the placenta and the liver.
Mentions: First, we aimed to detect the expression profile and levels of msFlt-1 in mice that had not received any viral injection. Total RNAs were isolated from placentas harvested on GD18, as well as from brain, kidney, liver, spleen, and uterine tissues harvested on PPD8. The expression of the endogenous transmembrane mFlt-1 mRNA was the highest in the placentas among the six tissues of mice that had not received virus injection (Figure 3A); msFlt-1-i13 mRNA expression was solely detected in the placentas of these non-treated animals (Figure 3B). Of note, the placental expression of msFlt-1-i13 mRNA was the highest among all tissues, genes and transcripts investigated in this study (Figure 3B). When we injected mice with the viral construct overexpressing the truncated msFlt-1(1-3), we observed the appearance of msFlt-1 mRNA expression in the liver (Figure 3B). The placental transcript levels of msFlt-1-i13 mRNA were not evidently increased in animals injected with the viral construct overexpressing truncated msFlt-1(1-3) compared to saline-treated mice, suggesting that the endogenous placental msFlt-1-i13 mRNA expression is higher than that of the transgene expressed msFlt-1(1-3) mRNA (Figure 3B).

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