Figure 2.

Early maternal and uterine vascular adaptations before the initiation of spiral artery flow. (A): Before implantation, the conceptus sheds products such as choriogonadotropin, interleukins, insulin-like growth factor (IGF) and extracellular vesicles. Proinflammatory interleukin 1β activates an endometrial inflammatory response, promoting apposition and adhesion at the implantation site with assistance of maternal insulin-like growth factor (IGF). (B): Fetal–maternal communication during implantation is illustrated by the release of embryonic lysophosphatidylcholine, which is metabolized by maternal autotaxin, promoting the invasion of the conceptus and the initiation of decidualization. This process involves loosening the intercellular connections and the release of trophic secretions, together with signals promoting inflammation, immune tolerance, and angiogenesis. Trophoblast cells modulate the functions of stromal cells, immune cells, natural killer cells, and endothelial cells by releasing proteolytic enzymes, paracrine and immunomodulatory agents, and extracellular vesicles. (C): Early stages of maternal vascular adaptation during the formation of the intervillous space. Spiral arteries are obstructed with trophoblast plugs and arterial blood is directed to the venous system via arteriovenous anastomoses. Simultaneously, the venular and lymphatic microcirculations are penetrated and modulated by trophoblast cells, promoting the release of gestational products into the maternal circulation and lymphatic system, weeks before the spiral artery flow actually starts. During this stage, the fetal environment is very hypoxic and growth of the conceptus is supported by maternal plasma products penetrating the trophoblast plugs, together with decidual histiotrophy. The three panels of this figure show that the abnormal adaptation of the uterine vasculature can result from an unbalanced inflammatory reaction, caused by inadequate signaling by the conceptus or a suboptimal maternal response. Abnormal remodeling of the venous and lymphatic vessels is responsible for the inefficient systemic distribution of adaptation signals and the inappropriate formation of the early intervillous space at the stage in which the spiral artery flow has not yet started.