**1. Introduction**

146 From Preconception to Postpartum

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Preeclampsia, a hypertensive disorder that complicates approximately 3-5% of first pregnancies and is usually clinically manifested after 20 weeks of gestation, is a major cause of perinatal morbidity and mortality; also, neonates of preeclamptic mothers are prone to preterm birth, low birth weight for gestational age and fetal growth restriction [Goldman-Wohl & Yagel, 2002]. Although the pathophysiologic process of preeclampsia is not fully elucidated, abnormal placentation, shallow endovascular invasion, placental hypoxia, maternal insulin resistance and diffuse endothelial dysfunction seem to be interconnected key events that may precede the clinical onset of the disease by weeks or months [Davison et al., 2004]. In particular, impaired placental perfusion is evident even from the first trimester as it has been documented by the findings of both histologic and Doppler ultrasound findings of the uterine arteries and the altered levels of placental derived biochemical markers as pregnancy-associated plasma protein (PAPP-A) [Poon et al., 2009a; Poon et al., 2009b].

The insulin-like growth factor (IGF) system comprises the IGF peptides (IGF-I, IGF-II), the cellular IGF receptors (type I, type II), and a family of soluble high affinity IGF binding proteins (IGFBP-1 to IGFBP-6) which modulate the bioavailability and activity of the IGFs [Jones & Clemmons, 1994] (Figure 1). Since the discovery of the IGF system before 50 or so years, there is ample evidence for their role in cell proliferation, differentiation and migration and their anti-apoptotic properties as well; thus they are involved in several physiological and pathological processes during prenatal and postnatal life [Forbes & Westwood, 2008]. This review aims to critically evaluate the postulated role of IGF axis components in the pathogenesis of preeclampsia and to discuss the mechanisms through which these effects are mediated.

#### **1.1 The IGF system in pregnancy**

During pregnancy, several alterations are noted regarding the expression pattern and function of IGFs. According to a recent longitudinal study, the maternal serum levels of IGF-I remain stable until 20 weeks and then increase whereas IGF-II values do not relatively change throughout gestation [Olausson et al., 2008]. Though in non-pregnant-individuals,

Recent Insights into the Role of the Insulin-Like Growth Factor Axis in Preeclampsia 149

Despite many similarities, IGFBPs have distinctive properties concerning their exact function, their constant hormonal and metabolic regulation, their structural features and the tissue distribution of their expression during the various stages of development. Although in the non-pregnant state, IGFBP-I is mainly produced in the liver, during pregnancy its predominant site of synthesis is the decidualized endometrium [Forbes & Westwood, 2008]. In particular, IGFBP-1 is increasing rapidly in maternal serum so as to be abundant in second- and third-trimester concomitantly with the second wave of trophoblast invasion until 35 weeks and then decrease thereafter till term [Olausson et al., 2008]. IGFBP-3, the most abundant binding protein for IGFs, provides a circulating storage reservoir for IGFs although its affinity may be decreased in gestation period. An endogenous pregnancyrelated serum IGFBP-3 proteolytic activity is considered a fundamental mechanism to increase bioactive IGFs [Lewitt et al., 1998]. Conflicting results have been reported regarding IGFBP-3 concentration throughout pregnancy probably as a result of different applied measurement methods; a recent longitudinal study reported that the maternal serum levels of IGFBP-3 remained stable and increased only after 35 weeks of gestation [Olausson et al., 2008]. The exact impact of IGFBPs also depends on the posttranslational modification of the protein (e.g. phosphorylation, glycosylation, altered proteolysis) which is under rapid and dynamic regulation [Forbes & Westwood, 2008]. Specifically, the IGFBP-I gene has multiple regulatory elements in its promoter that synergize or act independently and it is strongly regulated by insulin though IGFBP-3 is primarily determined by GH [Powell et al., 1995]. Besides, IGFBPs, particularly IGFBP-1, -3 and -5, carry out IGF-independent actions including inhibition of cell growth and induction of apoptosis; however their downstream

effects need further investigation [Cohen et al., 1993; Jones et al., 1993].

pathway mainly mitogenic [Frasca et al., 1999].

**2.1 The role of the IGF system in fetal growth** 

**2. IGF system in fetal growth and preeclampsia** 

The biological actions of both IGFs are mediated by binding to the two IGF receptors [Monzavi & Cohen, 2002]. The type I IGF receptor (IGF1R), a member of the protein tyrosine kinase receptor superfamily, is the main receptor for signal transduction and cellular action of the IGFs though the type II IGF receptor is identical to the mannose-6 phosphate receptor which shuttles lysosomal enzymes and binds IGF-II and (to a lesser extent) IGF-I [Monzavi & Cohen, 2002]. Another type of receptor which is also expressed in the placenta and binds to IGF-II in fetal tissues with similar affinity to IGF1R is the insulin receptor (IR) that is structurally similar to IGF1R but with a distinct signaling

An increasing wealth of literature including clinical and knockout studies in mice points to the crucial role of IGF axis in correct embryonic and placental development and growth. Regarding the role of IGF-I in fetoplacental growth, clinical studies based on the measurements in cord blood from healthy newborns demonstrated that birth weight is positively correlated with IGF levels and therefore, the levels are low and raised in small-for gestational-age (SGA) infants and large-for gestation-age (LGA) infants retrospectively [Giudice et al., 1995; Osorio et al., 1996; Boyne et al., 2003]. These clinical observations were further confirmed by studies using transgenic mice in which the mutation of the gene encoding either IGF-I or IGF-II resulted in restricted growth [Efstratiadis, 1998]. However, other research groups do not lend support to a relationship between total IGF-I and birth

growth

IGF-I is primarily derived from the liver, during gestation its main source is decidua under the stimulatory action of a specific growth hormone placental variant (PGH) that is produced by syncytiotrophoblast and extravillous trophoblast from the 7th or 8th week of gestation and gradually replaces pituitary growth hormone (GH) in the maternal circulation. PGH is implicated in the physiological adjustment to gestation by stimulating gluconeogenesis, lipolysis and anabolism and exercises its effects either indirectly by regulating IGF-I levels or in an autocrine/paracrine manner [Sifakis et al., 2009]. In plasma during postnatal life, most of the IGFs (75%) exist in a 140-k Da heterotrimeric complex consisting of IGFBP-3 and an -85 kDa protein, the acid-labile (ALS); when this complex dissociates, IGFs form smaller, binary complexes with the other IGFBPs while less than 1% of IGFs circulate in free biologically active form [Baxter, 1994].

Fig. 1. A simplified model of the components of the IGF axis and their role in placental development

IGF-I is primarily derived from the liver, during gestation its main source is decidua under the stimulatory action of a specific growth hormone placental variant (PGH) that is produced by syncytiotrophoblast and extravillous trophoblast from the 7th or 8th week of gestation and gradually replaces pituitary growth hormone (GH) in the maternal circulation. PGH is implicated in the physiological adjustment to gestation by stimulating gluconeogenesis, lipolysis and anabolism and exercises its effects either indirectly by regulating IGF-I levels or in an autocrine/paracrine manner [Sifakis et al., 2009]. In plasma during postnatal life, most of the IGFs (75%) exist in a 140-k Da heterotrimeric complex consisting of IGFBP-3 and an -85 kDa protein, the acid-labile (ALS); when this complex dissociates, IGFs form smaller, binary complexes with the other IGFBPs while less than 1%

**IGF-I**

**IR**

α

Fig. 1. A simplified model of the components of the IGF axis and their role in placental

α

β

IRS

**IGF-II**

GI F

IRS

α α

ββ β

B

**IGF1R IGF2R**

**MAPK PI3K**

**IGF-II** 

GI FB P

Extracellular

Cytoplasm

of IGFs circulate in free biologically active form [Baxter, 1994].

IG

**(+ / -) insulin PGH**

> **h CG IL-1β PAPP-A**

development

**progesterone**

F B P Despite many similarities, IGFBPs have distinctive properties concerning their exact function, their constant hormonal and metabolic regulation, their structural features and the tissue distribution of their expression during the various stages of development. Although in the non-pregnant state, IGFBP-I is mainly produced in the liver, during pregnancy its predominant site of synthesis is the decidualized endometrium [Forbes & Westwood, 2008]. In particular, IGFBP-1 is increasing rapidly in maternal serum so as to be abundant in second- and third-trimester concomitantly with the second wave of trophoblast invasion until 35 weeks and then decrease thereafter till term [Olausson et al., 2008]. IGFBP-3, the most abundant binding protein for IGFs, provides a circulating storage reservoir for IGFs although its affinity may be decreased in gestation period. An endogenous pregnancyrelated serum IGFBP-3 proteolytic activity is considered a fundamental mechanism to increase bioactive IGFs [Lewitt et al., 1998]. Conflicting results have been reported regarding IGFBP-3 concentration throughout pregnancy probably as a result of different applied measurement methods; a recent longitudinal study reported that the maternal serum levels of IGFBP-3 remained stable and increased only after 35 weeks of gestation [Olausson et al., 2008]. The exact impact of IGFBPs also depends on the posttranslational modification of the protein (e.g. phosphorylation, glycosylation, altered proteolysis) which is under rapid and dynamic regulation [Forbes & Westwood, 2008]. Specifically, the IGFBP-I gene has multiple regulatory elements in its promoter that synergize or act independently and it is strongly regulated by insulin though IGFBP-3 is primarily determined by GH [Powell et al., 1995]. Besides, IGFBPs, particularly IGFBP-1, -3 and -5, carry out IGF-independent actions including inhibition of cell growth and induction of apoptosis; however their downstream effects need further investigation [Cohen et al., 1993; Jones et al., 1993].

The biological actions of both IGFs are mediated by binding to the two IGF receptors [Monzavi & Cohen, 2002]. The type I IGF receptor (IGF1R), a member of the protein tyrosine kinase receptor superfamily, is the main receptor for signal transduction and cellular action of the IGFs though the type II IGF receptor is identical to the mannose-6 phosphate receptor which shuttles lysosomal enzymes and binds IGF-II and (to a lesser extent) IGF-I [Monzavi & Cohen, 2002]. Another type of receptor which is also expressed in the placenta and binds to IGF-II in fetal tissues with similar affinity to IGF1R is the insulin receptor (IR) that is structurally similar to IGF1R but with a distinct signaling pathway mainly mitogenic [Frasca et al., 1999].
