Preeclampsia shares common pathways with cardiovascular diseases. Pravastatin is a water soluble member of the statin family drugs, and does not cross the placenta. Our objective was to investigate the effect of pravastatin on the altered vascular function in a mouse model of preeclampsia induced by overexpression of sFlt-1.
At day (d) 8 of gestation, CD-1 mice were randomly allocated to injection of the adenovirus carrying Flt-1 (109 PFU) or mFc control (109 PFU) via the tail vein. Thereafter the pregnant mice were assigned to randomly receive pravastatin (Pra, 5 mg/kg/day dissolved in drinking water) or control; resulting in 4 groups: sFlt, sFlt-Pra, mFc and mFc-Pra. Mice were sacrificed at d18, and 2 mm segments of carotid artery were mounted in a wire myograph for isometric tension recording. Concentration-response (10−10M-10−5M) curves to acetylcholine (Ach), sodium nitroprusside (SNP), phenylephrine (PE) with or without L-NAME, and thromboxane A2 (TxA2) were obtained. Kruskal-Wallis and Mann-Whitney tests were used for statistical analysis.
sFlt-Pra mice had significantly lower contractile responses to PE compared to sFlt mice (max response 42.2±8.8 vs. 137.4±27.7, p=0.03) but not significantly different from the mFc group (p=0.23). The difference became non-significant with the addition of L-NAME. sFlt-Pra had a trend towards improved contractile responses to TxA2 compared to sFlt (p=0.06). The vasorelaxant responses to Ach were significantly higher in mFc-Pra compared to mFc (p=0.004) and sFlt (p<0.001). The responses to SNP were not significantly different. Plasma sFlt-1 levels were not different at baseline (d8), but were significantly lower in sFlt-Pra compared to sFlt at d18 (59.4±4.8 vs. 102.6±6.7 ng/ml; p=0.03) and similar to mFc control (p=0.52).
Administration of pravastatin to pregnant mice destined to develop preeclampsia ameliorates their vascular phenotype by decreasing the production of sFlt-1. Evaluation of statins for the prevention of the cardiovascular abnormalities of preeclampsia should be considered.
© 2009 Mosby, Inc. Published by Elsevier Inc. All rights reserved.