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Home » Biology Articles » Anatomy & Physiology » Physiology, Human » Control of human trophoblast function » Extravillous trophoblast function

Extravillous trophoblast function
- Control of human trophoblast function

EVT cells originating from the trophoblastic shell first enter the decidua and subsequently the myometrial stroma [3] as interstitial trophoblast. This encircles and destroys the smooth muscle cells of spiral artery media which is replaced by amorphous fibrinoid material. Subsequently, EVT expressing an endothelial phenotype invade the lumen of the arteries [46] to replace the endothelium of the vessels (Fig. 2).

Invasion of endometrial vessels by endovascular EVT is evident from 8 weeks onward, whereas myometrial artery invasion begins around the 14th week. This process mainly involves the vessels in the center of the placental bed, but also to a lesser extent the peripheral vasculature [47]. The expression of both angiopoietins and their receptor (Tie-2) has been observed during early placentation, suggesting an involvement of these regulatory agents in vascular remodeling. Moreover, the demonstration that Tie-2 is expressed on trophoblast suggests that angiopoietins may regulate its functions. For instance, it has been demonstrated that angiopoietins stimulate proliferation and migration of cultured cytotrophoblast and EVT cells, respectively [36]. Since the guinea pig interstitial trophoblast expresses NO synthases [48], a role for NO in dilating and remodeling uterine vessels has been hypothesized. However, human invasive trophoblast does not express NO synthesizing enzymes [49], and therefore it should not be able to release this vasoactive molecule. Another putative vasodilator is carbon monoxide, produced by hemoxygenase, whose expression has been demonstrated in all EVT cells [50]. Furthermore, molecules able to interact with each other have been identified in both NK and EVT cells [9]. In EVT cells MHC class I molecules are expressed, in particular HLA-C, E and G that are all good ligands for several members of the killer immunoglobulin receptor (KIR) family, present on NK cells. Such interaction modifies the NK cell cytokine repertoire and regulates adhesion molecules as well as matrix metalloproteinase (MMP) functionality [51]. Interstitial EVT cells move to the inner myometrium, where they fuse to become placental bed giant cells (GC) [52]. Since these multinuclear cells lose their ability to migrate and invade, their formation is likely to represent a mechanism which prevents deeper penetration into the uterine wall.

Invading EVT cells up-regulate the expression of proteins which favour uterine wall invasion, including MMPs, α5β1 and α1β1 integrins, VE-cadherin, and the trophoblast specific HLA class 1 molecule (HLA-G) which probably exerts a role in preventing fetal rejection. Conversely, these cells down-regulate the expression of adhesion molecules, such as α6β4 integrin or E-cadherin, unqualified for the invasion process, or of regulatory factors which inhibit cell invasiveness [53].

In addition to CT differentiation, O2 levels also influence EVT cell function. An inhibitory effect of hypoxia on EVT cell invasiveness has been reported [31,33,54], which is thought to be due to a modification of the integrin expression pattern which is, in turn, influenced by components of the ECM [54]. However, under different experimental conditions, an enhancement of trophoblast cell line invasiveness has also been observed [55]. This effect has been related to an enhanced expression of urokinase-type plasminogen activator (uPAR), an event which then results in the activation of plasmin and latent MMPs [55]. According to Genbacev et al [31] hypoxia does not inhibit cytotrophoblast differentiation/invasion before the 7th week of gestation.

Modulation of EVT function is a complex phenomenon which depends on a growing number of factors [13,56], beside those above described. However, the majority of available data were obtained from in vitro experiments, and contrasting responses may derive from different experimental conditions [57,58]. It is therefore impossible at present to describe the in vivo picture. Some of the key regulators of EVT functions are listed in Table 1.



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