Following implantation of the blastocyst, trophoblast cells begin to differentiate. Cytotrophoblast cells differentiate, migrate and invade into the uterine stroma in early pregnancy. The cytotrophoblast stem cells either fuse to form syncytiotrophoblasts or aggregate to form anchoring villous trophoblasts. The latter give rise to a sub-population known as extravillous trophoblasts which invade the uterine wall and its blood vessels, particularly the spiral arteries. The extravillous trophoblast cells remodel the maternal spiral arteries, displacing smooth muscle and endothelial cells, in order to produce a blood vessel with a larger diameter, increased blood flow and reduced resistance. This is an essential step in establishing and maintaining a normal pregnancy and is necessary for the higher blood requirement of the fetus later in pregnancy. The process of implantation, differentiation and invasion is illustrated below.




Our laboratory has demonstrated the importance of factors produced by different cells in the pregnant uterus including EGF and soluble HLA-G in inducing trophoblast migration. We have also demonstrated the ability of trophoblast to initiate apoptosis in spiral arteries via the Fas/Fas ligand and TRAIL pathway. The ability of trophoblast to evade apoptosis is key for spiral artery remodelling, and we have shown that this is partially due to an upregulation of nitric oxide synthase by trophoblast, and that this process is disrupted in trophoblast from pregnancies at a higher risk of pre-eclampsia.

Spiral Artery Invasion

Following implantation of the blastocyst into the endometrium the trophoblasts continue to invade the uterine endometrium until they reach the spiral arteries, by which time they have differentiated into an endothelial-like cell type. The trophoblasts then begin to remodel the spiral arteries by replacing the smooth muscle and endothelial cells. The result is an increase in vessel diameter and the creation of a high blood flow, low resistance zone. This process is illustrated below. The increased blood flow is essential for the developing embryo and a lack of spiral artery modification has been implicated in complications of pregnancy such as pre-eclampsia and intra-uterine growth retardation. The process of spiral artery remodelling is illustrated below.



As with any complex tissue, the development of the placenta is a highly regulated process. Nitric oxide is thought to be involved in many aspects of this regulation, including trophoblast apoptosis and motility.

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