**2.4.1 IGFBP-1**

A lot of controversy exists regarding the role and the precise mechanisms of action of IGFBP-I at the maternal-fetal interface. On the one hand, IGFBP-I may act as a maternal restrain to trophoblast invasion via its inhibitory effect on mitogenic IGFs in decidual microenvironment [Ritvos et al., 1998]. On the other hand, Gleeson et al. doubt these results showing that IGFBP-I potentiates directly the human trophoblast migration by binding of its RGD domain (Arg-Gly-Asp) to the α5β1 integrin/fibronectin receptor on invading trophoblast leading to activation of mitogen activated protein kinase (MAPK) pathway [Gleeson et al., 2001]. This hypothesis is consistent with the observation that the regulation of α3, α5, β1, β4 integrin subunits (classes of adhesion molecules receptors) in trophoblast cells is altered in preeclamptic pregnancies [Zhou et al., 1993]. In vivo, it is still questionable which pathway of IGFBP-1 action is deregulated resulting in net suppression on trophoblast invasion.

A possible source of this inconsistency is the altered post-translational modification of IGFBP-1 in pregnant women [Forbes & Westwood, 2008]. In the circulation of non-pregnant women, IGFBP-1 exists only in its phosphorylated state (p-IGFBP-1) with high affinity for IGFs whereas during pregnancy, IGFBP-1 is extensively dephosphorylated to nonphosphorylated and intermediately phosphorylated isoforms (np-IGFBP-I) with a 6-fold lesser binding affinity for IGF-I and similar affinity for IGF-II [Westwood et al., 1994]. The functional significance of this modification is highlighted by the finding that np-IGFBP-1 enhanced the metabolic actions of IGF-I in nutrient transport in contrast to the inhibitory phosphorylated isoform [Yu et al., 1998]. A more complete interpretation of the data requires consideration of the distribution of the phosphoisoforms of IGFBP-I accompanying preeclampsia in each trimester of pregnancy.

Recent Insights into the Role of the Insulin-Like Growth Factor Axis in Preeclampsia 155

further by IUGR demonstrating that this change may simply reflect low birthweight in these cases or alternatively the higher incidence of IUGR in severe preeclampsia [Wang et al., 1996].

In addition to the decidua basalis and parietalis, IGFBP-3, IGFBP-4, and IGFBP-5 are expressed in fetal cells with IGFBP-3 being the most prominent [Han et al., 1996]. Interestingly, the cleavage of IGFBP-3 into fragments during pregnancy except from increasing the availability of IGFs may have additional significance as in the same time these fragments can exert IGF-independent biological activity [Firth & Baxter, 2002]. Concerning the role of IGFBP-3 in preeclampsia, a study designed to detect genes associated to increased apoptosis in preeclamptic placentas showed a strong down regulation pattern leading to lower IGF-mediated anti-apoptotic effect causing placental dysfunction [Han et al., 2006]. In future, the interaction of some IGFBPs with other placental-produced factors should be also investigated. PAPP-A, a useful early marker of preeclampsia, has been identified as protease to IGFBP-3 and -4 so its lower levels observed in preeclampsia might diminish the amount

of IGFs being available for cell uptake and growth stimulation [Cowans et al., 2007].

IGFBP-3, the major carrier for IGFs in plasma during pregnancy is the only studied binding protein in maternal serum from preeclamptic pregnancies. The only so far published study that reported no change in IGFBP-3 levels in early stages of gestation is opposite to recent data that demonstrate an increase in IGFBP-3 concentration at 11-13 weeks in term but not in preterm preeclampsia not associated to uterine artery PI which is a known measure of impaired placental perfusion [Sifakis et al., 2011b]. Most likely, this finding could be the result of impaired glucose tolerance and increased insulin resistance as there is in vitro and in vivo evidence for a relationship between circulating IGFBP-3 levels and hyperglycemia and a IGFBP-3 potent insulin-antagonizing capability exerted either via IGF-independent pathways or by decreasing IGF-bioavailability. After the clinical establishment of preeclampsia, there is inconsistency among reported results as both a reduction and no change in its levels have been demonstrated [Altinkaynak et al., 2003; Wang et al., 1996].

Overall, it is still uncertain if the deregulation of the tuned balance among IGF system components possesses a crucial role in the pathogenesis of preeclampsia or is just a mere consequence of the disease. From this summary of relevant research, it is not yet plausible to determine the magnitude of possible associations, if any, between varying concentrations of IGFs and IGFBPs in maternal circulation and preeclampsia risk. Hopefully, the quantification of maternal plasma levels of the peptides of the IGF family may utilize as a predictive screening test to select pregnant women at increased risk for developing preeclampsia who may be favored from the administration of aspirin or other antiplatelet therapy or more intense sonographic surveillance, optimally as the only parameter or combined with other known independent indicators of preeclampsia risk. Clearly, much additional research is warranted including longitudinal studies with serial measurements of these factors and molecular clarification of the signaling pathways of each component intending to novel diagnostic interventions and to cast further light on the pathogenesis of

**2.4.2 Other IGFBPs** 

**3. Conclusion** 

preeclampsia as well.

De Groot et al. were the first who evaluated the midtrimester plasma level of IGFBP-1 in pregnancies destined to develop mild/moderate preeclampsia and observed lower circulating levels possibly due to the defective placentation that could affect the vascular deportation of this protein and/or its reduced hepatic synthesis [De Groot et al., 1996]. A more recent study underlined the fact that in a subgroup of women with coexisted White A diabetes the concentration of the protein was especially low even before the clinical manifestation of the two diseases [Hietala et al., 2000]. This notification implies that hyperinsulinemia, an important factor in the pathogenesis of preeclampsia, may additionally affect the level of serum IGFBP-1 although their association is still enigmatic.

In non pregnant women, IGFBP-I is negatively regulated by insulin and prevents glucose uptake by muscle and hepatic cells, possibly through IGF-dependent pathways [Holly et al., 1998]. Therefore decreased IGFBP-I have been related to various states of hyperinsulinemia including women with hypertension and insulin resistance. The interconnection of these two distinct entities is underlined by a series of well established clinical observations as that pregnancy-induced hypertension is more common in women with impaired glucose tolerance, pregnant women with diabetes have a higher incidence of preeclampsia and hyperinsulinemia can be detected in women several years after their first preeclamptic pregnancy [Suhonen & Teramo, 1993]. Surprisingly, other investigators have reported normal insulin response to intravenous glucose tolerance tests in preeclamptic women or even that these women were more sensitive to insulin [Solomon et al., 1994]. It is theorized that the negative relationship between insulin and IGFBP-1, typical of non-pregnant state, persists throughout normal pregnancy but seems to be lost in the early stages of pregnancies destined to become preeclamptic and either insulin starts to have a stimulatory effect on IGFBP-1 or both are regulated by another factor associated to preeclampsia such as hypoxia [Anim-Nyame et al., 2003]. However, in a longitudinal study, the circulating IGFBP-1 concentrations were found to be lower in serial samples obtained from women destined to develop preeclampsia indicating that IGFBP-1 is unlikely to act via its IGF-mediated effect and may actually promote trophoblast function acting through a signaling IGF-independent pathway [Anim-Nyame et al., 2000]. Concurrently, relatively low concentrations of IGFBP-1 both in the first and second trimesters were related to higher risk of term and in a lesser extent for preterm preeclampsia as it is noted in non-pregnant women with a higher prevalence of metabolic syndrome [Vatten et al., 2008]. This differentiation may further reflect two distinct clinical entities, as preterm preeclampsia is a clinically more severe form often accompanied by fetal restricted growth due to the placental disease in contrast to term preeclampsia in which placental perfusion and fetal growth are often normal and the main pathophysiological processes resemble those of the metabolic syndrome with an increase in adipose tissue and impaired glucose and lipid metabolism. these glucose

In pregnancies with established disease, IGFBP-1 levels are grossly elevated in the majority of the research studies with older studies supporting a positive correlation with severity of the disease and recent studies the opposite [Giudice et al., 1997; Ingec et al., 2004). This fluctuation in serum levels in relation to the clinical onset of preeclampsia has also been reported for other placental proteins, such as PAPP-A. Elevated circulating peptide levels may reflect the increased synthesis of IGFBP-1 from decidual cells which in turn may play a role in the shallow implantation, characteristic of preeclampsia. In another prospective study, IGFBP-I concentration was found augmented at the time of delivery only in preeclampsia complicated further by IUGR demonstrating that this change may simply reflect low birthweight in these cases or alternatively the higher incidence of IUGR in severe preeclampsia [Wang et al., 1996].
