Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia.
OBJECTIVE
To estimate the effects of pravastatin on the altered vascular function in a mouse model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase-1 (sFlt-1).


METHODS
Pregnant CD1 mice, at day 8 of gestation, were randomly allocated to injection using the tail vein of the adenovirus carrying sFlt-1 (10 plaque-forming units in 100 microliters; sFlt-1 group) or mFc (10 plaque-forming units) as virus control, and then to receive pravastatin (Pra; 5 mg/kg/d) dissolved in drinking water or control. The mice in four groups (sFlt-1, sFlt-1-pravastatin, mFc, and mFc-pravastatin; n=4-6 per group) were killed at day 18 of gestation and 2-mm segments of carotid artery were used for vascular reactivity studies. Serum sFlt-1 levels were also measured by enzyme-linked immunosorbent assay.


RESULTS
Mice in the sFlt-1 group had the highest responses to phenylephrine. Treatment with pravastatin decreased the contractile responses to phenylephrine (maximal effect [mean+/-standard error of the mean] 137.35+/- 27.70 compared with 42.24+/-8.76; P=.006) for sFlt-1 compared with sFlt-1-pravastatin, respectively. There were no differences in the contractile responses to thromboxane A2. The vasorelaxant responses to acetylcholine were significantly highest in the mFc-pravastatin group, with a maximal effect of 108.37+/-5.25 compared with 89.77+/-3.96 in the mFc group (P=.008), and those with sodium nitroprusside were not different across the four groups. Serum sFlt-1 levels were not different at baseline (day 8) but were significantly lower in sFlt-1-pravastatin compared with sFlt-1 at day 18 (59.42+/-5.31 compared with 102.59+/-15.15 ng/mL; P=.01).


CONCLUSIONS
Pravastatin improved the vascular reactivity in this murine model of preeclampsia by decreasing sFlt-1 levels. Statins should be evaluated for the prevention of the vascular abnormalities of preeclampsia.
Costantine
Maged M
MM
From the Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.
Tamayo
Esther
E
Lu
Fangxian
F
Bytautiene
Egle
E
Longo
Monica
M
Hankins
Gary D V
GDV
Saade
George R
GR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D005260:Female; D051379:Mice; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011225:Pre-Eclampsia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D011247:Pregnancy; D040281:Vascular Endothelial Growth Factor Receptor-1; D014666:Vasomotor System / Q000187:drug effects*
C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin; D000109:Acetylcholine