Maynard et al demonstrated that serum

Maynard et al. [54] demonstrated that serum levels of sFlt-1 were five times higher in pregnant women with PE than in normotensive women; as a consequence, VEGF and PlGF levels were found to be proportionally reduced in these women [54]. The literature confirms that there is a sharp increase in sFlt-1 levels between 11 and 5 weeks before the first signs of PE [52], [53], as well as a substantial reduction in PlGF and VEGF levels [53], whereas sEng levels increased significantly between 11 and 9 weeks before clinical signs [52], [61]. Experimental tests have showed that the increased synthesis of sFlt-1 inhibits angiogenic activity due to the blockade of endogenous functions of VEGF and PlGF, as well as physiological vasodilation. Furthermore, pregnant and non-pregnant rats were given a dose of recombinant adenovirus (responsible for the gene encoding of sFlt-1 mRNA) developed systemic hypertension, proteinuria and kidney injury, such as glomerular enlargement and glomerular fibrin deposits, capillary occlusion due to edema, hypertrophy of endocapillary cells, podocytes with protein Teicoplanin droplets, and effacement of podocyte foot processes, hence characterizing glomerular endotheliosis [54]. These findings are in agreement with other studies since in PE alone or in the concomitant presence of HELLP syndrome, the levels of Flt-1 mRNA increased 27.7 times, and Eng mRNA increased 6.9 times [76]; and there was a reduction of 85.4% in the expression of VEGF mRNA [77]. Moreover, Strevens et al. [78] found similar changes in renal biopsies from women with PE [78]. Laboratory tests have confirmed that PlGF serum levels are lower in pregnancies with severe PE (104pg/ml) or eclampsia (84.3pg/ml) in comparison with pregnancies without abnormalities (335.6pg/ml); as for sFlt-1 levels, a significant average increase was observed in severe EP (19,070.6pg/ml) or eclampsia (28,527.9pg/ml) when compared to normal pregnancies (6483.3pg/ml). A result similar to that of sFlt-1 was found regarding sEng in severe PE (37.2pg/ml) or eclampsia (46.7pg/ml) in comparison with pregnancies without changes (12.7pg/ml) [57], [79]. It should be noted that in early-onset PE (<34 weeks), the levels of PlGF appear to be significantly lower, with a difference of 500% in relation to late-onset PE (>34 weeks); as for sFlt-1, it has a higher level of early-onset PE, and it may reach a concentration difference of 600% in comparison with late-onset PE [52], [80]. In premature births, whose diagnosis of PE was confirmed, there was a reduction in PlGF levels in the first and second trimesters of pregnancy; whereas sFlt-1 and sEng levels, although lower in the first quarter, were substantially higher in the following quarter. Thus, it was possible to infer that pregnant women whose variation of PlGF was minimal or absent between the first and second trimester, and whose sFlt-1 and sEng levels increased continuously in the second trimester, were at high risk for PE [52], [53], [57], [61], [73], [74], [75], [81]. Studies have already showed that the synthesis of anti-angiogenic factors can be triggered by several stimuli. For example, the expression of endothelin-1, TNF-α and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA) is increased in PE and it promotes the synthesis of sFlt-1 and sEng, as well as proteinuria and systemic hypertension [82], [83]. Hypoxia, in turn, promotes the expression of hypoxia-inducible factor 1α (HIF-1α); and HIF-1α promotes the expression of TGF-β3, which acts as an antagonist of cytotrophoblast proliferation [72], [82], [84], [85]. Other factors have a significant influence on endothelial dysfunction, concomitantly to antiangiogenic factors. mRNA expression of the angiotensin II type 1 receptor and of angiotensin II is increased in chorionic villi, and it is responsible for the reduction of uteroplacental perfusion and vasoconstriction stimulation. Hence, the persistence of hypoxia, syncytiotrophoblast micro-particles in the circulation, and the increased expression of TNF-α [82] promote an exacerbated synthesis of IL-6, IL-16 and TNF-α, which also contributes to worsening the endothelial dysfunction present in this disease [25], [82]. Endostatin (fragment of collagen XVII), in turn, affects the interaction of VEGF with Filk-1 and, thus, interferes with the intracellular signaling pathways responsible for cell motility [50], [51]. Finally, the increased levels of matrix metalloproteinase-9 in the placenta seems to be associated with impaired extracellular matrix (ECM) degradation during angiogenesis, as well as with cytotrophoblast invasion in PE [51].