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. 2013 May;61(5):1103-10.
doi: 10.1161/HYPERTENSIONAHA.111.00226. Epub 2013 Mar 4.

Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension

Ashley J Bauer  1 , Christopher T Banek, Karen Needham, Haley Gillham, Susan Capoccia, Jean F Regal, Jeffrey S Gilbert
Affiliations

Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension

Ashley J Bauer et al. Hypertension. 2013 May.

Abstract

Preeclampsia is a pregnancy-specific condition characterized by an imbalance of circulating angiogenic factors and new-onset hypertension. Although current treatment options are limited, recent studies suggest that pravastatin may improve angiogenic profile and reduce blood pressure in preeclampsia. We hypothesized pravastatin would restore angiogenic balance and reduce mean arterial pressure (MAP) in rats with reduced utero-placental perfusion pressure (RUPP)-induced hypertension. Pravastatin was administered intraperitoneally (1 mg/kg per day) in RUPP (RUPP+P) and normal pregnant rats (NP+P) from day 14 to 19 of pregnancy. On day 19, MAP was measured via catheter, conceptus data were recorded, and tissues collected. MAP was increased (P<0.05) in RUPP compared with NP dams, and pravastatin ameliorated this difference. Pravastatin attenuated decreased fetal weight and plasma vascular endothelial growth factor and the RUPP-induced increased soluble fms-like tyrosine kinase-1 when compared with NP dams. Pravastatin treatment did not improve angiogenic potential in RUPP serum and decreased (P<0.05) endothelial tube formation in NP rats. RUPP rats presented with indices of oxidative stress, such as increased placental catalase activity and plasma thiobarbituric acid reactive substances along with decreased plasma total antioxidant capacity compared with NP controls, and pravastatin attenuated these effects. MAP, fetal weight, plasma vascular endothelial growth factor, and plasma soluble fms-like tyrosine kinase-1 were unchanged in NP+P compared with NP controls. The present data indicate that treatment with pravastatin attenuates oxidative stress and lowers MAP in placental ischemia-induced hypertension, but may have negative effects on circulating angiogenic potential during pregnancy. Further studies are needed to determine whether there are long-term deleterious effects on maternal or fetal health after pravastatin treatment during pregnancy-induced hypertension or preeclampsia.

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Figures

Figure 1
Figure 1. Mean arterial pressure (MAP)
Pravastatin decreased blood pressure compared to untreated reduced utero-placental perfusion pressure (RUPP) rats, but was higher than normal pregnant (NP) controls. Data are expressed as mean ± SEM, * indicates p<0.05.
Figure 2
Figure 2. Fetal weight, fetal resorptions, placental efficiency and heart weight
Fetal weight (Panel A) was decreased in reduced utero-placental perfusion pressure (RUPP) compared to normal pregnant (NP). Pravastatin administration resulted in fetuses that were not smaller than fetuses from NP dams or from NP dams treated with pravastatin. There were an increased number of fetal resorptions in the RUPP compared to the NP rats and pravastatin had no effect in either group (Panel B). Placental efficiency was decreased by RUPP and this was ameliorated by pravastatin (Panel C). Heart weight was increased by RUPP and this was ameliorated by pravastatin (Panel D). Data are expressed as mean ± SEM, * indicates p<0.05.
Figure 3
Figure 3. Circulating Cytokines and Anti-angiogenic Factors
Circulating sFlt-1 (Panel A) was increased and VEGF (Panel B) was decreased in reduced utero-placental perfusion pressure (RUPP) compared to normal pregnant (NP) controls. Pravastatin administration restored the sFlt-1:VEGF ratio to NP levels (Panel C). Panel D shows that TNF-α was increased in the RUPP+P group compared to NP rats. Data are expressed as mean ± SEM, * indicates p<0.05. TNF-α was square root transformed prior to analysis.
Figure 4
Figure 4. Plasma TBARS and trolox antioxidant capacity
Plasma levels of TBARS (Panel A) were increased and antioxidant capacity (Panel B) was decreased in reduced utero-placental perfusion pressure (RUPP) compared to normal pregnant (NP) rats. Pravastatin restored both TBARS and antioxidant capacity to NP levels. Data are expressed as mean ± SEM, * indicates p<0.05.
Figure 5
Figure 5. Placental catalase activity
Catalase activity was increased in reduced utero-placental perfusion pressure (RUPP) compared to normal pregnant (NP) rats. Treatment with pravastatin lowered catalase activity in the RUPP dams. Data are expressed as mean ± SEM, * indicates p<0.05.
Figure 6
Figure 6. Effects of pravastatin on endothelial cell (EC) tube formation
Panel A shows that EC tube formation was decreased in reduced utero-placental perfusion pressure (RUPP) rats compared to normal pregnant (NP) controls. Pravastatin treatment had no effect in RUPP rats and decreased EC tube formation in NP rats compared to NP controls. Panel B shows that when 20 μM pravastatin was added directly to NP and RUPP serum post-mortem to determine if there were direct effects on EC tube formation EC tube formation was decreased in reduced utero-placental perfusion pressure (RUPPs) compared to normal pregnant (NPs) controls. Pravastatin did not directly affect EC tube formation (RUPPs+P, NPs+P). Data are expressed as mean ± SEM, * indicates p<0.05.
Figure 7
Figure 7. Effects of oxygen concentration and pravastatin on vascular endothelial growth factor (VEGF) secretion by BeWo and JEG trophoblast cells
BeWo cells secreted increased (panel A) concentrations of VEGF in hypoxic (1.5% O2) conditions with and without pravastatin (Prav), thus the main statistical effect was due to O2 concentration. In contrast, JEG cells decreased (panel B) VEGF secretion with pravastatin treatment and showed no effect of O2 concentrations. Data are expressed as mean ± SEM, * indicates p<0.05.
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