EVT cells originating from the trophoblastic shell first enter the decidua and subsequently the myometrial stroma 
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  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 .
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 . Since the guinea pig interstitial trophoblast expresses NO synthases ,
a role for NO in dilating and remodeling uterine vessels has been
hypothesized. However, human invasive trophoblast does not express NO
synthesizing enzymes ,
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 . Furthermore, molecules able to interact with each other have been identified in both NK and EVT cells .
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 . Interstitial EVT cells move to the inner myometrium, where they fuse to become placental bed giant cells (GC) .
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 .
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 .
However, under different experimental conditions, an enhancement of
trophoblast cell line invasiveness has also been observed .
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 . According to Genbacev et al  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.