Karen Needham

Pravastatin Attenuates Hypertension, Oxidative Stress, and Angiogenic Imbalance in Rat Model of Placental Ischemia-Induced Hypertension

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.

Exercise Training Attenuates Placental Ischemia-Induced Hypertension and Angiogenic Imbalance in the Rat

An imbalance between proangiogenic (vascular endothelial growth factor) and antiangiogenic (soluble fms-like tyrosine kinase 1) factors plays an important role in hypertension associated with reduced uteroplacental perfusion (RUPP). Exercise has been shown to stimulate proangiogenic factors, such as vascular endothelial growth factor, in both the pregnant and nonpregnant state; thus, we hypothesized that exercise training would attenuate both angiogenic imbalance and hypertension attributed to RUPP. Four groups of animals were studied, RUPP and normal pregnant controls and normal pregnant and RUPP+exercise training. Exercise training attenuated RUPP-induced hypertension (P<0.05), decreased soluble fms-like tyrosine kinase 1 (P<0.05), increased VEGF (P<0.05), and elevated the soluble fms-like tyrosine kinase 1:vascular endothelial growth factor ratio. The positive effects of exercise on angiogenic balance in the RUPP rats were confirmed by restoration (P<0.05) of the RUPP-induced decrease in endothelial tube formation in human umbilical vascular endothelial cells treated with serum from each of the experimental groups. Placental prolyl hydroxylase 1 was increased (P<0.05) in RUPP+exercise training rats. Decreased trolox equivalent antioxidant capacity in the placenta, amniotic fluid, and kidney of the RUPP rats was reversed by exercise. RUPP-induced increase in renal thiobarbituric acid reactive species was attenuated by exercise. The present data show that exercise training before and during pregnancy attenuates placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress in the RUPP rat and reveals that increased prolyl hydroxylase 1 is associated with decreased soluble fms-like tyrosine kinase 1, thus revealing several potential pathways for exercise training to mitigate the effects of placental ischemia-induced hypertension. Lastly, the present study demonstrates that exercise training may be a useful approach to attenuate the development of placental ischemia-induced hypertension during pregnancy.

AICAR administration ameliorates hypertension and angiogenic imbalance in a model of preeclampsia in the rat.

Previous studies suggest restoration of angiogenic balance can lower blood pressure and improve vascular endothelium function in models of preeclampsia. Our laboratory has recently reported exercise training mitigates hypertension in an animal model of preeclampsia, but the mechanisms are unknown. AMP-activated protein kinase (AMPK) is stimulated during exercise and has been shown to increase expression of VEGF. Therefore, the purpose of this study was to determine whether AICAR (5-aminoimidazole-4-carboxamide-3-ribonucleoside), a potent AMPK stimulator, would increase circulating VEGF, improve angiogenic potential, decrease oxidative stress, and abrogate placental ischemia-induced hypertension. In rats, reduced uteroplacental perfusion pressure (RUPP) was induced on day 14 of gestation by introducing silver clips on the inferior abdominal aorta and ovarian arteries. AICAR was administered intraperitoneally (50 mg/kg b.i.d.) days 14-18, and blood pressure and tissues were collected on day 19. RUPP-induced hypertension was ameliorated (P < 0.05) with AICAR versus RUPP. AICAR increased (P < 0.05) plasma VEGF and decreased (P < 0.05) plasma soluble VEGF receptor-1 in the RUPP + AICAR versus RUPP. Antioxidant capacity was restored (P < 0.05) by AICAR in RUPP placenta. Renal and placental catalase activity was decreased (P < 0.05) in RUPP + AICAR versus RUPP. Angiogenic potential was increased (P < 0.05) in RUPP + AICAR versus RUPP. Fetal and placental weights were unaffected by AICAR. Placental AMPK phosphorylation was increased (P < 0.05) in RUPP + AICAR versus normal pregnant and RUPP. These findings suggest AICAR may be useful to mitigate angiogenic imbalance, renal, and placental oxidative stress and increase in blood pressure associated with RUPP hypertension. Furthermore, placental AMPK phosphorylation was observed only in the setting of ischemia.