Pravastatin Corrects Endothelial Dysfunction in Ex Vivo Uterine Radial Arteries in Preeclampsia.

AIM: Endothelium-dependent relaxation in isolated uterine radial arteries from normotensive (NT) and preeclamptic (PE) pregnancies, and the acute effects of pravastatin in the latter vessels were assessed. Pravastatin is hypothesized to alleviate endothelial dysfunction in PE via modulating aspects of NO and endothelium-derived hyperpolarization-mediated relaxation.

METHODS

Radial arteries isolated from the uterus of NT and PE pregnant patients were incubated with pravastatin (2 mM/6 h), methyl-β-cyclodextrin (10 mM/1 h) in vitro, or vehicle. Vessel function was determined with pressure myography, while related morphology and protein/mRNA expression were characterized using immunohistochemistry, electron microscopy, and qPCR.

RESULTS

Endothelium-dependent, bradykinin-induced NO-mediated relaxation was impaired in radial arteries from PE compared to NT pregnancy, with a reduced intermediate- and large-conductance Ca2+-activated K+-channel contribution. Endothelial small-conductance Ca2+-activated K+-channel function and expression were increased in arteries from PE, compared to NT patients. Pravastatin restored NO and endothelium-derived hyperpolarization-mediated relaxation in arteries from PE women; potentially overcompensating overall endothelium-dependent relaxation. Myoendothelial gap junction and endothelial caveolae density, and caveolin-1 and endothelial-NOS expression were decreased in arteries from PE relative to NT pregnancies and increased following pravastatin incubation. Caveolae density in NT patient arteries was reduced by methyl-β-cyclodextrin, while endothelial caveolae were increased in vessels from PE patients. Pravastatin incubation restored endothelial function via improved NO and endothelium-derived hyperpolarization-type mechanisms.

CONCLUSIONS

Pravastatin restored endothelium-dependent relaxation in uterine radial arteries from PE pregnancies. Data support the therapeutic potential for pravastatin in treating PE, with ongoing trials determining the validity of its use in the clinical setting.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01717586.