Reduction of circulating soluble Flt‐1 alleviates preeclampsia‐like symptoms in a mouse model

Abstract

Preeclampsia (PE) is characterized by widespread endothelial damage with hypertension, proteinuria, glomeruloendotheliosis and elevated soluble Flt-1 (sFlt-1), a natural occurring antagonist of vascular endothelial growth factor (VEGF). Cancer patients receiving anti-VEGF therapy exhibit similar symptoms. We suggested that a decrease in circulating sFlt-1 would alleviate the symptoms associated with PE. Adenoviral (Adv) overexpression of sFlt-1 induced proteinuria, caused glomerular damage and increase in blood pressure in female Balb/c mice. Circulating level of sFlt-1 above 50 ng/ml plasma induced severe vascular damage and glomerular endotheliosis. Albumin concentration in urine was elevated up to 30-fold, compared to control AdvGFP-treated animals. The threshold of kidney damage was in the range of 20–30 ng/ml sFlt-1 in plasma (8–15 ng/ml in urine). Co-administration of AdvsFlt-1 with AdvVEGF to neutralize circulating sFlt-1 resulted in more than a 70% reduction in free sFlt-1 in plasma, more than 80% reduction in urine and rescued the damaging effect of sFlt-1 on the kidneys. This demonstrates that below a critical threshold sFlt-1 fails to elicit damage to the fenestrated endothelium and that co-expression of VEGF is able to rescue effects mediated by sFlt-1 overexpression.

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

“…(3) Administration of recombinant VEGF-121 for treatment of preeclampsia in experimental animals can lead to reduction in sFlt-1 concentrations in the circulation, clinical reduction in blood pressure, histopathological improvement in endothelial function and decreased placental hypoxia. (15,16) The studies of Li et al, (15) Bergmann et al, (20) Gilbert et al, (21) Mateus et al, (16) and Woods et al, (7) on administration of VEGF-121 in experimental animals show similar significant results, such as reduced systolic blood pressure and reduced renal damage. In the present study mean VCAM-1 expression in the group of murine preeclampsia models given recombinant VEGF-121 was significantly lower than in the group of murine preeclampsia models alone.…”

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…This directive applies especially to VEGF supplementation in the gravid female because of a myriad of adverse fetal effects from VEGF overexposure that have been observed in animal models 81, 82, 83, 84, 85, 86. Previous studies using free VEGF‐A isoforms, including VEGF‐A 165 87, 88, 89 and VEGF‐A 121 ,36, 64, 90, 91 have demonstrated therapeutic efficacy in treating the maternal syndrome of preeclampsia. In these previous studies, VEGF was administered in vitro,88 by chronic infusion,36, 64 or via adenoviral vector overexpression 31, 87, 89, 90, 91.…”

“…Previous studies using free VEGF‐A isoforms, including VEGF‐A 165 87, 88, 89 and VEGF‐A 121 ,36, 64, 90, 91 have demonstrated therapeutic efficacy in treating the maternal syndrome of preeclampsia. In these previous studies, VEGF was administered in vitro,88 by chronic infusion,36, 64 or via adenoviral vector overexpression 31, 87, 89, 90, 91. However, David et al raise the concern that adenoviral delivery of VEGF to the mother may risk harming the fetus by breeching the placental barrier 89.…”

Renal Effects of Preeclampsia

“…On the other hand, exogenous administration of VEGFA alleviates this preeclampsia-like phenotype in rats without apparent harm to the fetus [20]. Likewise, renal damage induced in mice by adenoviral overexpression of sFlt1 is alleviated by reducing circulating sFlt1 through co-expression of VEGF [21].…”