Recombinant Vascular Endothelial Growth Factor 121 Attenuates Autoantibody-Induced Features of Pre-eclampsia in Pregnant Mice

Background Circulating levels of sFLT‐1 (soluble fms‐like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non‐pregnant female mice were exposed to air or to Br 2 at 600 ppm for 30 minutes and were treated with vehicle or with VEGF‐121 (100 μg/kg, subcutaneously) daily, starting 48 hours post‐exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post‐exposure. In Br 2 ‐exposed pregnant mice, there was a time‐dependent and significant increase in plasma levels of sFLT‐1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF‐121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br 2 . Exogenous VEGF‐121 administration had no effect in non‐pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT‐1 overexpression as a mechanism of pregnancy‐specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.

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Vascular endothelial growth factor (VEGF) receptors 1 and 2 gene expression is up‐regulated in the cervix of pregnant mice treated with lipopolysaccharide (LPS).

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.767.7 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Morgan Paige Thompson ◽

Chishimba Nathan Mowa

Keyword(s):

Gene Expression ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Vascular Endothelial ◽

Vegf Receptors ◽

Pregnant Mice ◽

Endothelial Growth Factor

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Recombinant vascular endothelial growth factor 121 decreases vascular cell adhesion molecule-1 in murine pre-eclampsia model placenta

Zinc supplementation improves heme biosynthesis in rats exposed to lead ◽

10.18051/univmed.2016.v35.192-198 ◽

2016 ◽

Vol 35 (3) ◽

pp. 192

Author(s):

Sri Sulistyowati ◽

John Arianto Sondakh ◽

Eric Edwin Yuliantara ◽

Supriyadi Hari Respati ◽

Soetrisno Soetrisno

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cell Adhesion Molecule ◽

Angiogenic Factor ◽

Vascular Endothelial ◽

Vascular Cell Adhesion ◽

Vascular Cell ◽

Pregnant Mice ◽

Cell Adhesion Molecule 1 ◽

Endothelial Growth Factor

Background Preeclampsia is one of the major contributors to maternal and fetal morbidity and mortality. Imbalance of soluble Fms-like tyrosine kinase (sFlt-1) as anti-angiogenic factor and vascular endothelial growth factor (VEGF) as pro-angiogenic factor plays a role in the pathogenesis of preeclampsia. Endothelial dysfunction in preeclampsia causes vascular cell adhesion molecule-1 (VCAM-1) to be expressed on its surface. This study aims to evaluate the effect of recombinant VEGF-121 on VCAM-1 expression in the placenta of a murine preeclampsia model. Methods An experimental analytical study conducted from February until March 2016 in the Biomedical Laboratory, Faculty of Veterinary Medicine, Airlangga University. The study sample consisted of 30 pregnant mice, divided into three groups, i.e. 10 normal pregnant mice, 10 mice with preeclampsia model and 10 mice with preeclampsia model and recombinant VEGF-121 therapy. All animals were subjected to immunohistochemical examination of VCAM-1 expression in their placentas. The results were assessed semiquantitatively according to a modified Remmele method. Data analysis was done using one-way ANOVA and Tukey’s multiple comparisons method. Results Mean VCAM-1 expression in normal (0.97 ± 0.54%) murine placentas, compared with placentas (2.94 ± 0.96%) of murine preeclampsia models (p=0.000), while mean VCAM-1 expression in placentas of murine preeclampsia models with VEGF intervention was 2.14 ± 0.68% (p=0.030). Conclusion Recombinant VEGF-121 can reduce VCAM-1 expression in placentas of murine preeclampsia models. The present study has shown the potential benefits of VEGF therapy, justifying serious consideration of this therapeutic approach for use in women with preeclampsia.

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Alternative Splicing of Vascular Endothelial Growth Factor (VEGF)-R1 (FLT-1) pre-mRNA Is Important for the Regulation of VEGF Activity

Molecular Endocrinology ◽

10.1210/mend.13.4.0265 ◽

1999 ◽

Vol 13 (4) ◽

pp. 537-545 ◽

Cited By ~ 118

Author(s):

Yulong He ◽

Stephen K. Smith ◽

Kate A. Day ◽

Dawn E. Clark ◽

Diana R. Licence ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Alternative Splicing ◽

Growth Factor ◽

Binding Activity ◽

Vascular Endothelial ◽

Mammalian Development ◽

Mouse Cdna ◽

Pregnant Mice ◽

Endothelial Growth Factor

Abstract Angiogenesis is essential for normal mammalian development and is controlled by the local balance of pro- and antiangiogenic factors. Here we describe a novel mouse cDNA sequence encoding sFLT-1 that is a potent antagonist to vascular endothelial growth factor (VEGF) and show for the first time its in vivo production. In situ hybridization and Northern blot analysis with probes specific for sFLT-1 or FLT-1 showed that the relative abundance of their mRNAs changed markedly in spongiotrophoblast cells in the placenta as gestation progressed. On day 11 of pregnancy, sFLT-1 mRNA was undetectable but FLT-1 readily apparent, and by day 17 sFLT-1 mRNA was abundant but FLT-1 barely detectable. sFLT-1 was identified in conditioned medium of cultured placenta from day 17 pregnant mice and likely to be present in the circulation, as there is a substantial increase of VEGF-binding activity in the serum from day 13 of pregnancy, which coincides with the abundant sFLT-1 expression in placenta. Expression of sFLT-1 was also observed in adult lung, kidney, liver, and uterus. These data suggest a novel mechanism of regulation of angiogenesis by alternative splicing of FLT-1 pre-mRNA. Treatment of pregnant mice with exogenous VEGF from day 9 to 17 of pregnancy, which alters the ratio of VEGF to sFLT-1, resulted in an increase in the number of resorption sites and fibrin deposition in the placenta of ongoing pregnancies. These findings have important implications for understanding placental function and may be relevant in a range of disease states.

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Recombinant vascular endothelial growth factor 121 injection for the prevention of fetal growth restriction in a preeclampsia mouse model

Journal of Perinatal Medicine ◽

10.1515/jpm-2016-0149 ◽

2017 ◽

Vol 45 (2) ◽

Cited By ~ 2

Author(s):

Sri Sulistyowati ◽

Muhammad Adrianes Bachnas ◽

Nuri Dyah Anggraini ◽

Eric Edwin Yuliantara ◽

Wisnu Prabowo ◽

...

Keyword(s):

Experimental Study ◽

Vascular Endothelial Growth Factor ◽

Birth Weight ◽

Growth Factor ◽

Potential Role ◽

Vascular Endothelial ◽

Fetal Birth Weight ◽

Pregnant Mice ◽

Endothelial Growth Factor

AbstractAim:To discover the potential role of recombinant VEGFSubjects and methods:This is an experimental study of 30 pregnant mice that were randomly divided into three groups: normal, PE, and PE with rVEGFResults:On average, fetal birth weight was 0.7150 g in the normal group, 0.4936 g in the PE group, and 0.6768 g in the PE with rVEGFConclusions:Injection of rVEGF

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