Maternal and placental adaptations to hypoxia

Abstract

Oxygen is an essential element that is required to sustain life. Oxygen is especially important in the maintenance of pregnancy where proper oxygen delivery to the fetus is crucial. In order to study pregnancy-dependent responses, a physiological stressor such as hypoxia was used to exaggerate pregnancy-induced vascular remodeling, which induced maternal adaptive responses to protect the fetus. In this dissertation, we describe studies designed to evaluate cellular and molecular mechanisms underlying maternal adaptations to hypoxia during the establishment of the hemochorial placenta. Therefore, studies focused on the effects of low oxygen tension on in vivo and in vitro trophoblast cell gene expression and vascularization at the maternal-fetal interface.

Our hypothesis is that in vivo, hypobaric hypoxia, defined as a low oxygen environment regulated by differential gas pressure, will induce maternal and placental-driven responses that are responsible for compensatory mechanisms facilitating oxygen delivery to the fetus. We observed changes in placental gene expression, uteroplacental vasculature, maternal red blood cell parameters, and splenic gene expression. The uteroplacental compartment was identified as a site of drastic adaptive responses, including alteration in the growth and patterns of gene expression in the chorioallantoic placenta and increases in vascularity within the uterine mesometrial compartment. Uterine mesometrial blood vessels were more numerous and their diameters expanded in animals exposed to hypoxia. The majority of the centrally-located vessels retained smooth muscle actin, unlike the disappearance of smooth muscle associated with the uterine spiral arteries of late gestation. Maternal hypoxia also stimulated uterine mesometrial nitric oxide synthase-3 (Nos3) expression, a factor potentially contributing to the hypoxia-induced uterine vascular dilation.

Collectively, these studies demonstrate the importance of various maternal and placental adaptive responses to hypoxia which permits proper oxygen delivery to the fetus allowing successful maintenance of pregnancy. We propose that these adaptive mechanisms are crucial in our in vivo model of pregnancy and hypoxia and may be disrupted in pregnancy-associated diseases such as preeclampsia and intrauterine growth restriction, which are more prevalent in high altitude pregnancies.