2 a syndrome highly reminiscent of human PE: hypertension and proteinuria due to a glomerular endotheliosis [14, 16]. Similarly, sEng is a truncated form of receptor for two subtypes of transforming growth factor beta (TGFβ) specif- ically, TGFβ1 and TGFβ2 which are highly expressed by vas- cular endothelial cells and syncytiotrophoblasts. Like sFlt1, soluble endoglin (sEng) is an antiangiogenic factor capable of inhibiting capillary tube formation in vitro [17]. Soluble Eng also increases vascular permeability; overexpression of both sFlt1 and sEng in rodents results in capillary permeability in the lungs, kidneys, and liver [18]. Overexpression of both sEng and sFlt1 in pregnant rats develops nephrotic-range proteinuria, severe hypertension, biochemical evidence of HELLP (“H” for hemolysis, “EL” for elevated liver enzymes, and “LP” for low platelet count), and intrauterine growth restriction of the pups [19, 20]. PlGF concentration during pregnancy increases during the ﬁrst 30 weeks of gestation, and then decreases [13]. Longitudinal studies have shown that a relatively low PlGF concentration (which could be explained by a high sFlt1 con- centration) is also a characteristic feature of PE. Decreased levels of urinary PlGF and PIGF : sFlt-1 ratio during mid- gestation have been proposed as a predictive model for development of clinical PE, and quantiﬁcation of sFlt-1 levels has correlated directly with severity of disease and inversely with time to onset of proteinuria and hypertension [21]. The exact molecular basis for placental dysregulation of these factors remains unknown but hypoxia is likely an important regulator [22]. Other factors such as alterations in the renin-angiotensin-aldosterone axis, immune maladap- tion, excessive shedding of trophoblast debris, oxidative stress, and genetic factors likely contribute to the pathogen- esis of the abnormal placentation [22]. To date the most successful treatment for PE is delivery. 3. Preeclapmpsia and Cathecol-O-methyltrasferase Cathecol-O-methyltrasferase (COMT) catalyzes the O- methylation of various circulating hormones such as cate- cholamines and catecholestrogens [23, 24]. In the placenta, COMT metabolizes certain forms of circulating estradiols to the molecule 2-methyl estradiol (2-ME). This estradiol metabolite has several eﬀects, one being the destabilization of hypoxia-inducible factor- (HIF-) 1α3 in the cytoplasm. HIFs are heterodimeric proteins that mediate the eﬀects of hypoxia on gene expression by upregulating transcription of target genes including sFlt1 [25]. This role of COMT in main- taining oxygen balance suggests that COMT might some- how be involved in the pathogenesis of PE. To better elucidate the role of COMT in PE, a genetic COMT knockout (COMT−/−) mouse model was recently developed. Interestingly, pregnant COMT−/− mice devel- oped a PE-like phenotype characterized by proteinuria, in- creased blood pressure, and histopathological changes in the placenta and kidney. This phenotype was accompanied by lower plasma concentrations of 2-ME and higher placental protein levels of HIF-1a [26]. Restoration of 2-ME in Journal of Pregnancy COMT−/− mice decreased HIF-1a and ameliorated the preeclamptic phenotype [26]. Together, these results suggest that COMT and 2-ME deﬁciency might play a signiﬁcant role in the development of PE. The exact mechanism by which 2-ME prevents PE re- mains unknown. Although 2-ME was found to suppress HIF-1a and sFlt1, recent experiments suggest that there might be several other mechanisms through which 2-ME promotes vascular health [27]. Lastly, recent evidence suggests that 2-ME is necessary for cytotrophoblast invasion of the maternal decidua and therefore contributes to the prevention of PE by promoting normal placental vascular formation [28]. Further studies on this topic will be required to ascertain a more exact mech- anism of action. 4. PE and Complement Factors The complement system, composed of over 30 proteins that act in concert to protect the host against invading organisms, initiates inﬂammation and tissue injury [29] and normally has a protective role toward oﬀ-infection. Complement ac- tivation promotes chemotaxis of inﬂammatory cells and generates proteolytic fragments that enhance phagocytosis by neutrophils and monocytes. There is scant information about complement activation in normal and abnormal human pregnancy [30]. During normal gestation, serum levels of C3, C4, and total hemolytic complement (CH50) gradually increase 10%–50% [31]. Studies have shown sig- niﬁcant elevations in levels of Bb, C3a, C4d, and soluble C5b- 9 in preeclampsia, indicating excess activation of both the classical and alternative complement pathway [32]. Lynch et al. conducted a large prospective study in human preg- nancy to investigate whether elevated levels of complement activation fragment Bb (reﬂecting alternative complement pathway activation) at a single point in early pregnancy (less than 20 weeks gestation) were predictive of preeclampsia later in pregnancy. Adjusted for other risk factors, women with higher levels of Bb in early pregnancy were almost four times more likely to develop preeclampsia later in pregnancy compared with women with levels less than the top decile in early pregnancy [33]. Products of complement pathway have been found in deciduas, chorionic villi, and as subendothelial deposits in vessel walls in normal and preeclampsia [34, 35]. A recent study reported that the presence in C5b-9 MAC on trophoblasts was associated with ﬁbrin deposits at sites of villous injury in vivo in normal placentas, but especially in placentas from pregnancies complicated by IUGR or preeclampsia [36]. It has been demonstrated that in normal pregnancies, complement regulatory proteins that are highly expressed on trophoblast membranes pre- vent excessive complement activation (membrane cofactor protein [MCP (CD46)], decay accelerating factor [DAF (CD55)], and CD59)) as well as circulating complement reg- ulatory proteins (complement factor H [CFH], C4b binding protein, and complement factor I [CFI]) [37, 38]. Defective regulation of the complement system allows for the excessive complement activation that leads to placental damage,