Vascular remodeling at the maternal-fetal interface: Placental interactions with uterine blood vessels and the lymphatic circulation during pregnancy

The placenta induces important vascular changes in the uterus during pregnancy that allow the mother to adequately support growth and development of the embryo/fetus. Specifically, the uterine vasculature must incorporate the placenta into the maternal circulation facilitating mechanical attachment and nutrient/waste exchange. As they invade the uterine wall, placental cytotrophoblasts remodel resident blood vessels in a manner that channels maternal blood to and from the placenta. Although both sides of the circulation are involved in this process, remodeling is biased towards uterine spiral arterioles. An ultrastructural (scanning electron microscopy) study that was completed as a part of this thesis dramatically illustrates the unusual nature of this process.; Here, we show that EphB4 and ephrinB2, venous and arterial cell surface receptors, respectively, are involved in patterning cytotrophoblast interactions with maternal blood vessels. As they invade the uterine wall, cytotrophoblasts switch from a venous to and an arterial phenotype downregulating EphB4 expression and sequentially upregulating ephrinB1 and -B2. In vitro, the cells avoid EphB4-coated substrates and decrease their migration in response to 3T3 cells expressing this molecule. EphB4 inhibited migration by regulating chemokine-induced movement rather than a growth factor-stimulated response. These data suggest that, in the uterine wall, EphB4, expressed on maternal veins, restricts cytotrophoblast venular invasion, ultimately resulting in preferential remodeling of arterial vessels.; To further study cytotrophoblast-blood vessel interactions, we developed a novel in vivo model of human placentation. Implantation of placental anchoring villous explants into the mammary fat pads or under the kidney capsules of SCID mice gave rise to a cytotrophoblast population that breached murine blood vessels. Histological analyses of these hybrid tissues revealed multiple aspects of vascular remodeling including the impact of the placenta on the arterial and lymphatic vasculature. We also show that pregnancy induces an astonishingly robust lymphangiogenic response in the uterine wall since the non-pregnant endometrium normally lacks a lymphatic circulation. Thus, we provide evidence that the placenta establishes an endometrial lymphatic circulation during pregnancy, the functional consequences of which likely involve fluid regulation and maternal-fetal immunity. (Abstract shortened by UMI.)...