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

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 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 i.p. (1 mg/kg/day) in RUPP (RUPP+P) and normal pregnant rats (NP+P) from day 14-19 of pregnancy. On day 19, MAP was measured via catheter, conceptus data was recorded and tissues collected. MAP was increased (p<0.05) in RUPP compared to NP dams and pravastatin ameliorated this difference. Pravastatin attenuated decreased fetal weight and plasma VEGF and the RUPP-induced increased sFlt-1 when compared to 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 TBARS along with decreased plasma total antioxidant capacity compared to NP controls and pravastatin attenuated these effects. MAP, fetal weight, plasma VEGF, and plasma sFlt-1 were unchanged in NP+P compared to 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 if there are long-term deleterious effects on maternal or fetal health following pravastatin treatment during pregnancy-induced hypertension or preeclampsia.

Differential Effects of Complement Activation Products C3a and C5a on Cardiovascular Function in Hypertensive Pregnant Rats

“…In the RUPP model, decreased VEGF could also potentially result in decreased complement control proteins, allowing increased complement activation as demonstrated in kidney endothelium (Mason et al, 2004;Kerr and Richards, 2012). Although a recent study by Weissgerber et al (2014) questions the validity of the enzyme-linked immunosorbent assay for measurement of VEGF in rat plasma and serum, our previous studies have reported decreased angiogenic potential via endothelial tube formation assays in RUPP compared with normal pregnant controls (Gilbert et al, 2012b;Bauer et al, 2013). Clearly, a re-evaluation of the methodology for assessing angiogenic factors in the rat circulation is needed, with additional studies to understand the relationship between angiogenic imbalance and complement activation/control proteins following placental ischemia.…”

Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension

“…For instance, trials with pravastatin are underway to ameliorate preeclampsia by inhibiting HMG CoA reductase, but because statins are contraindicated in pregnancy, as this class of drugs has a high risk of teratogenic potential 27 . Interestingly, the mechanistic rationale for pravastatin use is its potential to up-regulate VEGF and PlGF and correct the angiogenic imbalance of excess sFlt-1 in RUPP rats 28 . While this rationale is consistent with our therapeutic approach, administering rhPlGF is likely to be a more direct and safer strategy to treat preeclampsia.…”

Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia

“…14,15 However, the move to clinical trials is perhaps surprising given all the preclinical mechanistic evidence pointing to pravastatin as a therapeutic has been performed in animal models. [16][17][18][19] Work examining whether pravastatin has any biological effects in relevant human tissues is extremely limited. One recent study suggested that low-dose pravastatin has no effect on sFlt-1 or sENG secretion from placental explants obtained from 3 term preeclamptic women.…”

“…[16][17][18][19] Surprisingly, in contrast to simvastatin, there has been little investigation into the effect of pravastatin on primary human tissues. It would be important to confirm whether pravastatin can in fact reduce sFlt-1 in primary human tissues or in placentas obtained from women with preeclampsia.…”