Aberrations in the soluble angiogenic factors have been described in pregnancy complications such as preeclampsia and intrauterine fetal growth restriction.
The last decade has seen a plethora of publications investigating the role of angiogenic factors in placental disease, in particular the VEGF family, and their receptor levels in the maternal circulation. While it is evident that the angiogenic factors and their receptor levels are aberrant in placental disease, whether there are differences between preeclampsia with and without IUGR and isolated IUGR is not clear. It is still not established whether these changes are part of the pathogenesis of placental disease or a reactionary change to the disease process in the placenta.
1.10.4.1 VEGF-A in preeclampsia
Although VEGF plays an important role in placental angiogenesis, the serum or plasma level of VEGF-A has not been a reliable marker for identification of pathological pregnancies. The commercially available ELISA kits measure the free VEGF-A, which is the biologically active form. The measurable levels in the maternal blood have been documented to be below the detection levels of the assay (206-208). The few studies measuring total VEGF have demonstrated elevated VEGF levels in preeclamptic pregnancies as compared to normotensive pregnancies (205, 209-211). These findings suggest that the total circulating VEGF-A may be increased in preeclamptic pregnancies and that the free level is reduced due to binding to the soluble receptor sFlt-1. Soluble Flt-1 binds VEGF-A with a higher affinity than PlGF, resulting in extremely low circulating levels of free VEGF-A (75).
1.10.4.2 soluble fms like tyrosine receptor-1 (sFlt-1) in preeclampsia
Elevated sFlt-1 levels have been shown to be a feature of preeclampsia and are proposed to play a significant role in the pathogenesis of the condition by causing an anti-angiogenic state and endothelial dysfunction in the maternal circulation. Further support for this hypothesis is provided by the fact that the incidence of preeclampsia is increased in mothers carrying Trisomy 13 fetuses (212). The genes for sFlt-1 and Flt-1 are localized to chromosome 13 and maternal circulating levels of sFlt-1 have been demonstrated to be elevated in Trisomy 13 (213).
The first documentation of circulating elevated sFlt-1 in preeclampsia was by Clark et al 1998 (179), followed by Maynard et al in 2003 (155) in a study that demonstrated that placental soluble fms-like tyrosine kinase 1 (sFlt1) is up regulated in preeclampsia, leading to increased systemic levels of sFlt-1 that fall after delivery. Based on these data the increased circulating sFlt1 levels in patients with preeclampsia were suggested to decrease circulating levels of free
VEGF and PlGF and inhibit their biological activities. Considerable evidence have been published on elevated serum sFlt-1 levels in preeclamptic pregnancies both prior to (214, 215) and at the time of clinical diagnosis (155, 178, 205, 215), as well as several reviews on the role of pro and anti-angiogenic factors in preeclampsia (24, 187, 216, 217). In a retrospective study, Levine et al. (215) reported that soluble Flt-1 is elevated in mid-pregnancy in preeclamptic patients 5 weeks before clinical symptoms were observed, and that there is a strong correlation between the level of soluble Flt-1 in maternal serum and the pathological degree of preeclampsia. In a review of 34 studies on soluble markers of preeclampsia, the
Major sites of placental sFlt-1 expression are degenerative syncytiotrophoblasts known as syncytial knots (179). Whether the excess sFlt-1 is contributed to by other cell types such as macrophages in the placenta or monocytes in the maternal or fetal peripheral circulation has not been explored.
The pathophysiology of up regulation of sFlt-1 in pre-eclampsia and pregnancy complications and whether it is a second order phenomenon is still to be completely understood. It has been postulated that soluble Flt-1 secreted from the trophoblast layer between the maternal and fetal blood vessels plays an important role in creating a barrier of ‘VEGF-low’ layer between the fetal and maternal sides in normal pregnancy. Unusual stress such as hypoxia in placenta or viral infection may induce abnormal expression of soluble Flt-1, which, in turn, blocks
physiological VEGF in various tissues at maternal side, and induces tissue dysfunction such as proteinuria (96).
Soluble Flt-1 overexpression in rats has been shown to result in the characteristic clinical features of preeclampsia, hypertension, proteinuria and glomerular endotheliosis. The anti-angiogenic state induced by excess placental production of sFlt-1 can be ‘rescued’ by administering VEGF-A and PlGF (155).
1.10.4.3 Placental growth factor (PlGF) in preeclampsia
Studies into the PlGF levels in normal pregnancy have documented a steady increase in serum PlGF during the first two trimesters, a peak at 29–32 weeks and a decline towards full term (206, 215). Published studies have shown serum PlGF levels to be significantly lower than normal pregnancies in early onset preeclampsia less than 37 weeks compared with late onset preeclampsia, severe disease compared with mild disease and in preeclampsia associated with fetal growth restriction (215, 220). Measured urinary PlGF levels have been shown to have similar profiles to the serum levels in normal and preeclamptic pregnancies (221). Maternal serum PlGF is known to be reciprocal to the levels of sFlt-1 (215).
1.10.4.4 soluble Kinase Domain Receptor (sKDR) in preeclampsia
Several studies have investigated the levels of the soluble form of the KDR receptor (sKDR) in human plasma. Maternal plasma sKDR is reduced in preeclampsia and in growth-restricted pregnancies (222-224) compared to non-pregnant and normal pregnancy levels.
1.10.4.5 soluble Endoglin (sEng) in preeclampsia
Literature to date on Endoglin in pregnancy has shown that the soluble form of Endoglin is elevated in preeclampsia and may play a significant role in the pathogenesis of the disease (188, 223, 225, 226). Placental expression and peripheral levels of sEng are up-regulated in
preeclampsia with the levels correlating with disease severity and falling after delivery. Over-expression of sEng in pregnant rats leads to increased vascular permeability and hypertension without proteinuria. These effects are amplified by co-administration of sFlt-1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and fetal growth restriction (170). These findings suggest that sEng may act in gradually with increasing gestation in normal pregnancy and the development of preeclampsia (188). This increase in sEng is associated with an increase in the ratio of sFlt-1: PIGF and the composite biomarker (sFlt-1+ sEng): PIGF has been suggested to be predictive of preeclampsia (188).
1.10.5 Soluble angiogenic markers in small for gestational age (SGA) / intrauterine fetal