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  • Therefore VEGF and its receptors are expressed in different

    2024-02-07

    Therefore, VEGF and its receptors are expressed in different organs, including the kidneys, the liver and the CC-223 [55]. In the human placenta, VEGF is mainly synthesized by cytotrophoblast and Hofbauer cells early in the first trimester, whereas Flk-1 and Flt-1 receptors are expressed throughout the placenta, mainly in cytotrophoblasts. Studies indicate that the activation of Flk-1 and Flt-1 receptors would trigger signaling pathways associated with endothelial migration and proliferation, as well as vascular permeability, formation, tubular ramification and maintenance of blood vessels; whereas Flt-4 would be related to the development of lymphatic vessels. Because sFlt-1 has antiangiogenic properties, when it binds to VEGF and PlGF, it prevents their interactions with Flt-1 and Flk-1 receptors [5], [49]. PlGF, in turn, has been described to be expressed in four isoforms (PlGF-1, PlGF-2, PlGF-3 and PlGF-4), which play a key role in vasculogenesis throughout the embryonic development. In the placenta, this factor is first detected in the syncytiotrophoblast, and serum levels increase from the 30th week with subsequent decrease in normotensive pregnancies [13]. Endoglin, also known as CD105, is a membrane-bound protein that acts as a coreceptor for TGF-β1 and TGF-β3. It consists of an extracellular domain, a single transmembrane domain, and a short cytoplasmic domain and, similarly to Flt-1, it also has a soluble isoform (sEng) that has antiangiogenic properties [5], [57], [58]. Endoglin has a little expression in quiescent endothelial cells, but a significant expression in stromal cells, hematopoietic stem cells, proliferative endothelial cells, and in the syncytiotrophoblast [5]; it inhibits apoptosis and activates the synthesis of endothelial nitric oxide [13]. Therefore, it is capable of inducing cell migration and proliferation [5], [59]. It is believed that in breast and colo-rectal neoplasias sEng is formed through the action of metalloproteinase-14 in the transmembrane domain of endoglin; however maintains its extracellular domain and thus the ability to bind to TGF-β and BMP-9. Metalloproteinase-14 is also expressed in syncytiotrophoblast and in PE acts on endoglin of placental cells. Research has shown that the greater expression of inhibitors of this metalloproteinase attenuates the synthesis of sEng by placenta [5], [59], [60]. In circulation, both sFlt-1 and sEng interact with their respective binders (VEGF, PlGF and TNF-β), impairing the binding of these pro-angiogenic molecules to their native endothelial cell-surface receptors. Thus, elevated serum levels of sFlt-1 and sEng, and reduced serum levels of PlGF are observed in the PE [53], [54], [59], [61], [62]. According to a research, plasma concentrations of sFlt-1(41.5±15.8 vs 6.11±3.3ng/ml) and sEng (86.8±38.3 vs 13.4±6.1ng/ml) in women with PE were significantly higher in relation to those normotensive; in contrast, PlGF (96.1±46.4 vs 508.2±332.3pg/ml) presented a significant reduction in relation to normotensive pregnant women [62]. Thus, it is clear that placentation is dependent on the balance between the expression of angiogenic and antiangiogenic factors throughout pregnancy. The expression of VEGF-A, PlGF, endoglin, and their receptors, Flt-1, Flk-1, sFlt-1 and sEng, appears to be essential for the establishment of uteroplacental circulation and for fetal development [63], [64]. Studies have showed that VEGF-A, VEGF-B and PlGF are responsible for modulating cytotrophoblast proliferation, differentiation and invasion via Flt-1 and Flk-1 receptors; since when promoting placental angiogenesis, they also promote the expression of coreceptor neuropilin-1, contributing to the enhancement of VEGF-A activity through interaction with Flk-1. As for endoglin, not only does it contribute to the formation of new blood vessels, but also to the regulation of muscle tone [51]. There is a higher expression of sFlt-1 in the placenta of PE patients, so increased maternal serum concentration of this substance is noticeable. On the other hand, a lower expression of VEGF-A and PlGF is observed, since sFlt-1 binds to both factors in the circulation and prevents interaction with endogenous receptors [53], [54], [65], [66], [67], [68]. In addition to these changes, the serum concentration and the mRNA expression of sEng are increased; and because sEng competes with the endogenous receptor when binding to TGF-β, both the vasculogenesis and placental angiogenesis of pregnant women with PE are impaired [51], [69], [70], [71], [72]. Due to intense endothelial dysfunction, both antiangiogenic factors (Flt-1 and sEng) can be detected in the maternal circulation early in the first trimester of pregnancy, prior to the first clinical signs of disease [51], [52], [53], [61], [73], [74], [75].