Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment

Abstract

During placentation invasive extravillous trophoblasts (EVTs) migrate into the maternal uterus and modify its vessels. In particular, remodeling of the spiral arteries by EVTs is critical for adapting blood flow and nutrient transport to the developing fetus. Failures in this process have been noticed in different pregnancy complications such as preeclampsia, intrauterine growth restriction, stillbirth, or recurrent abortion. Upon invasion into the decidua, the endometrium of pregnancy, EVTs encounter different maternal cell types such as decidual macrophages, uterine NK (uNK) cells and stromal cells expressing a plethora of growth factors and cytokines. Here, we will summarize development of the EVT lineage, a process occurring independently of the uterine environment, and formation of its different subtypes. Further, we will discuss interactions of EVTs with arteries, veins and lymphatics and illustrate how the decidua and its different immune cells regulate EVT differentiation, invasion and survival. The present literature suggests that the decidual environment and its soluble factors critically modulate EVT function and reproductive success.

Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

“…Thus, the studies on the roles of decidual immune cells have been focused on the suppression of semi-allogenic fetus rejections in the establishment of pregnancy. Additionally, recent studies show that decidual immune cells are necessary for angiogenesis in the establishment of pregnancy [68]. For example, decidual NK cells secrete angiogenic factors, such as VEGF, angiopoietin-2, placental growth factor (PlGF), and chymase [69,70].…”

The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

“…Proper placental development is essential for a successful pregnancy. In the first trimester of pregnancy, the placenta develops in a low oxygen environment [12]. NFκB is activated by the inflammation and hypoxia that occurs in early pregnancy.…”

Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems

“…60 Decidualized stromal cells also express a wide array of growth factors and cytokines and thereby exert developmental effects on the conceptus. 61 Immune cells of the decidua protect the embryo from being attacked by maternal immune cells and together with decidualized stromal cells regulate the development of the trophoblast lineage. As a result, they regulate the depth of invasion of the implanting embryo and placenta, ensuring their adequate attachment to the uterus.…”

“…As a result, they regulate the depth of invasion of the implanting embryo and placenta, ensuring their adequate attachment to the uterus. 61,62 To regulate invasion, decidualized stromal cells must exhibit motility to accommodate the embryo and placenta 63,64 but eventually must act as a physical and biochemical barrier to prevent the villi from becoming too deeply attached in the uterus and in some cases even to adjacent organs like the bladder. An abnormally firmly attached placenta, a condition that affects 1 in 2,500 pregnancies, not only results in hemorrhage during pregnancy but is a major cause of postpartum hemorrhage and is associated with significant maternal morbidity and mortality.…”