Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Fetoplacental glucocorticoid overexposure is a significant mecha- nism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β- HSD2) plays a key role. We previously discovered that Hsd11b2−/− mice, lacking 11β-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2+/+, Hsd11b2+/−, and Hsd11b2−/− littermates from heterozygous (Hsd11b+/−) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for ma- ternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2−/− fetuses did not un- dergo the normal gestational increase seen in Hsd11b2+/+ litter- mates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11β-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2−/− fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ame- liorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2−/− fetuses. This im- proved cardiac function occurred despite persisting indications of in- creased glucocorticoid exposure in the Hsd11b2−/− fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction. placenta