Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis

摘要

Adequate maternal vascular adaptations and blood supply to the uterus and placenta are crucial for optimal oxygen and nutrient transport to growing fetuses of eutherian mammals, including humans. Multiple factors contribute to hemodynamics and structuring of placental vasculature essential for term pregnancy with minimal complications. In women, failure to achieve or sustain favorable pregnancy progression is, not surprisingly, associated with high incidence of antenatal complications, including preeclampsia, a hypertensive disorder of pregnancy. While the pathogenesis of preeclampsia in women remains unknown, a role for androgens is emerging. The relationship between androgens and maternal cardiovascular and placental function deserves particular consideration because testosterone levels in the circulation of preeclamptic women are elevated approximately two- to three-fold and are positively correlated with vascular dysfunction. Preeclampsia is also associated with elevated placental androgen receptor (AR) gene expression. Studies in animal models mimicking the pattern and level of increase of adult female testosterone levels to those found in preeclamptic pregnancies, replicate key features of preeclampsia, including gestational hypertension, endothelial dysfunction, exaggerated vasoconstriction to angiotensin II, reduced spiral artery remodeling, placental hypoxia, decreased nutrient transport and fetal growth restriction. Taken together, these data strongly implicate AR-mediated testosterone action as an important pathway contributing to clinical manifestation of preeclampsia. This review critically addresses this hypothesis, taking into consideration both clinical and preclinical data.