Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications

Abstract

Figure 8. Effects of placental sFlt1 knockdown with or without endometrial VEGF overexpression. (A-L) Placental sFlt1 knockdown. Upon placentaspecific sFLT1 shRNA expression, widespread hemorrhaging in the fetus (B) and at the placental-decidual junction (D) was observed on GD18 compared with controls (A and C). Histological examination of sFLT1 shRNA-expressing placentas revealed extraordinary dilation of some maternal blood sinuses (arrowheads) in the labyrinth (E and F) and fibrin deposition (arrow) in these spaces (G and H). (I and J) MSB staining revealed extravasated fibrin (arrow) in adjacent areas. Placental sFlt1 knockdown did not affect implantation rate (K), whereas the fetal resorption rate significantly increased (L). (M-V) Placental sFlt1 knockdown enhanced the deleterious effects in Endo-VEGF animals. Pregnancies surviving to GD16 exhibited (M) excessive vaginal bleeding and (N-P) termination of pregnancy or resorption (arrows denote resorption sites) as well as (Q) widespread and extensive hemorrhaging in fetuses and placentas (arrowheads) and in deciduas at the maternal-fetal junction (asterisk). Histological examination (R-T) revealed widespread dilation and congestion of maternal blood sinuses (arrowheads) in the labyrinth, venous sinuses, and veins at maternal-fetal junctions, and MSB staining (U and V) demonstrated extensive fibrin extravasation (arrows) in the labyrinth and at the maternal-fetal junction. Results are mean ± SD. *P < 0.05 (n = 15). Scale bars: 2 mm (A-D); 500 μm (E, F, and R); 50 μm (G-J); 100 μm (S-V).

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

“…The therapeutic dose range of ELP‐VEGF (1–5 mg/kg per day) is equivalent to a free VEGF dose of 187 to 932 μg/kg per day because of the differences in molecular weight between the free and ELP‐fused cytokine. The efficacy observed at these doses is consistent with previous studies using the free cytokine, which showed normalization of blood pressure at doses in the range of 180 to 400 μg/kg per day 36, 64. The ameliorative effect of ELP‐VEGF on mean arterial pressure may be the result of 2 possible mechanisms.…”

“…Studies using viral overexpression33, 57, 59, 60, 61 or direct infusion of sFlt‐132, 55, 62, 63 have demonstrated a critical role for this anti‐angiogenic factor for induction of hypertension and renal damage during pregnancy. Previous studies using exogenous VEGF infusion have reported reduced circulating sFlt‐1 levels 36, 64. However, induction of local VEGF expression in the maternal decidua was shown to actually promote increased placental sFlt‐1 expression in the cytotrophoblasts,65 suggesting a protective role for placental sFlt‐1 against maternal overproduction of VEGF 66.…”

“…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.…”

Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

“…In this regard, overexpression of sFlt-1 by decidual cells produces a PE-like syndrome in mice (53). Finally, a decidualization defect could help explain our previous finding that isolation and culture of CTBs from sPE placentas reversed the gene dysregulation that was initially observed (9).…”