title: Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess.
abstract: Fetoplacental glucocorticoid overexposure is a significant mechanism 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 maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. 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, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased 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.
authors.affiliation: School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, WA 6009, Australia; caitlin.wyrwoll@uwa.edu.au.
authors.forename: Caitlin S
authors.initials: CS
authors.lastname: Wyrwoll
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: June
authors.initials: J
authors.lastname: Noble
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Thomson
authors.affiliation: School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, WA 6009, Australia;
authors.forename: Dijana
authors.initials: D
authors.lastname: Tesic
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Rog-Zielinska
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Moran
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, WA 6009, Australia; Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Holmes
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000502:physiology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005938:Glucocorticoids / Q000378:metabolism*; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010922:Placenta Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017035:Pravastatin / Q000494:pharmacology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000924:Anticholesteremic Agents; D005938:Glucocorticoids; D012333:RNA, Messenger; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C000609895:HSD11B2 protein, mouse; D017035:Pravastatin
keywords: 11β-HSD2; developmental programming; fetal heart; glucocorticoids; placenta