3. Umbruch 4.4..2005 - Online Pot

Endocannabinoids and regulation of fertility 69
It can be proposed that down-regulation of FAAH during early pregnancy
might allow higher local levels of AEA, which indeed have been shown to
increase with pregnancy in the mouse uterus [5]. In turn, AEA might play a
role in the endometrial changes associated with pregnancy, for instance
through the inhibition of gap junctions and intercellular calcium signalling
[21, 22]. On the other hand, nanomolar concentrations of AEA inhibit embryo
development and blastocysts hatching in vitro [5, 20, 23]. This suggests that
the local concentration of AEA around the implanting embryos must be low,
implying that the blastocysts have the biochemical tools to dispose AEA and
to prevent its detrimental effects. Indeed, AMT and FAAH activity have been
demonstrated and characterized in these cells [20]. Moreover, AEA-induced
inhibition of embryo development and blastocyst hatching is prevented by a
CB 1 receptor antagonist, in line with the hypothesis that this activity of AEA
is mediated by CB 1 receptors [3].
Collectively, these findings lead to a dual function of AEA in regulating fertility
in mammals, a scenario that is schematically depicted in Figure 1. On one
hand, a decreased FAAH activity in mouse uterus during early pregnancy
might allow higher levels of AEA at the inter-implantation sites. Here,
enhanced AEA can be instrumental in modifying endometrium by inhibiting
gap junctions. On the other hand, a low level of AEA has to be granted at the
implantation sites, in order to reduce the toxic effects of this lipid to the blastocysts.
The reduction of AEA levels can be achieved by the active AMT and
FAAH expressed by blastocysts, as well as by the uterine epithelial cells. It
seems noteworthy that dual functions of AEA, depending upon its local concentration,
have been already proposed to explain its anti-proliferative (high
AEA) or pro-proliferative (low AEA) effects on trophoblast growth at the
inter-implantation and implantation sites, respectively [18]. Consistently, AEA
has been shown to regulate blastocyst function and implantation within a very
narrow concentration range, by differentially modulating mitogen-activated
protein kinase signalling and calcium channel activity via CB 1 receptors [24].
The embryo–uterine interactions are further complicated by the recent finding
that mouse blastocysts rapidly (within 30 min of culture) release a soluble
compound that increases by approximately 2.5-fold the activity of FAAH
present in the mouse uterus without affecting gene expression at the translational
level [25]. This “FAAH activator” is not present in uterine fluid, is
released by neither dead blastocysts nor mouse embryonic fibroblasts, and is
produced by trophoblast and inner cell-mass cells. Moreover, its activity is
fully neutralized by lipase and is further potentiated by trypsin, whereas other
proteases, phospholipases A 2, C or D, DNase I or RNase A are ineffective.
Interestingly, the blastocyst-derived activator does not affect PLD, CB receptors
or AMT in mouse uterus, pointing to a selective action towards FAAH. As
yet the FAAH activator, the first ever reported to our knowledge, has not been
identified with any factor known to be released by blastocysts, like
platelet-activating factor, leukotriene B 4 or prostaglandins E 2 and F 2α, and its
molecular identity remains elusive [25]. However, the fact that a specific