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18: Regulation of placental and renal hypoxia gene expression by VEGF121 therapy in a mouse model of preeclampsia induced by sFlt-1 overexpression

      Objective

      HIF-1α and TGFβ-3 expression is upregulated while CGM1 expression is downregulated under hypoxic conditions. We aimed to determine the effect of VEGF121 therapy on the expression of these genes in the placenta and kidney in an animal model of preeclampsia induced by overexpression of sFlt-1.

      Study Design

      At day 8 of gestation, CD-1 mice were randomly allocated to subcutaneous insertion of osmotic minipumps prepared with VEGF121 (n=8) or phosphate buffered-saline solution (PBS) as a solvent-control (n=4). Pumps were calibrated to deliver 400μg/kg/day or equivalent PBS for 10 days. At day 9, VEGF121 mice were randomly allocated to tail vein injections with Adv-sFlt-1 (109 PFU) or mFc (109 PFU) as virus-control (n=4/group). PBS-mice were treated with Adv-sFlt-1 (109 PFU). Animals were sacrificed on day 18. mRNA expression of HIF-1α, TGFβ-3, and GCM1 was measured by real time polymerase chain reaction (RT-PCR). Kruskal-Wallis test was used for statistical analysis (significance: p<0.05).

      Results

      Placental HIF-1α expression was significantly higher in the PBS-sFlt-1 mice than in the VEGF-sFlt-1 and the VEGF-mFc mice (relative expression (RE) 2.38 ± 0.39 vs 0.88 ± 0.26 and 1.05 ± 0.09; p=0.01). Placental TGFβ-3 expression level was higher in the PBS-sFlt-1 mice as compared to the VEGF-sFlt-1 mice (RE 2.22 ± 0.58 vs 0.69 ± 0.18; p=0.04). Placental and renal GCM1 expression levels were significantly higher in the VEGF-mFc than in the PBS-sFlt-1 mice (RE 4.81 ± 0.74 and 2.49 ± 0.46 vs 2.14 ± 0.03 and 0.69 ± 0.22; p<0.05). Renal and placental GCM1 and renal HIF-1α expression did not differ significantly between the PBS-sFlt-1 and the VEGF-sFlt-1 mice.

      Conclusions

      VEGF121 effectively reversed the changes in several hypoxia-related genes in the placenta. Our findings confirm that angiogenic imbalance plays a role in preeclampsia. Therapy with pro-angiogenic factors has the potential to improve placental function.