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An in vitro assay in which endothelial cells
An in vitro assay in which endothelial cells form 3D tube-like structures was used to investigate effects of dNK on vessel stability. The results indicate that dNK cells from women with high spiral artery resistance index had reduced ability to activate endothelial cells, since endothelial cells presented lower expression of ICAM-1 and TNF-α, compared with endothelial cells activated by dNK from women with normal spiral artery resistance index. Consequently, there will also be impairment in remodeling of uterine edu kit [42].
The higher levels of syncytiotrophoblast micro-particles in the maternal circulation also seems to contribute to a systemic inflammatory response, leading to increased production of inflammatory mediators [9], [29], [43], [44]. It is important to note that hypoxia associated with placental insufficiency causes oxidative stress, which is when there is an increased synthesis of reactive oxygen species (e.g. peroxynitrite, hydrogen peroxide, hydroxyl radical) and reduction of antioxidant synthesis (e.g. superoxide dismutase, glutathione, vitamin C) [21], [30].
These reactive oxygen species lead to lipid peroxidation and, hence, the synthesis of toxic byproducts (lipid peroxide, malondialdehyde, and lipid hydroperoxide), and severe damage and dysfunction of the vascular endothelium, which is associated with increased synthesis of inflammatory mediators and with change in the serum levels of angiogenic and antiangiogenic factors [21], [45], [46], [47], such as soluble receptor tyrosine kinase, soluble endoglin, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) [1], [13], [21], [47], [48].
Angiogenic and antiangiogenics factors
The placenta is an organ that is highly vascularized by maternal and fetal blood vessels, and its development, maturation and functions depend on efficient vasculogenesis (de novo formation of new blood vessels), on angiogenesis (the formation of new blood vessels from other pre-existing vessels), and on cytotrophoblast invasion for spiral artery remodeling, which is called pseudo-vasculogenesis [49], [50], [51].
In normal pregnancies, the expression of different molecules, such as integrins, cadherins and metalloproteinases, allows the cytotrophoblast to switch from an epithelial to an endothelial cell phenotype, thereby stimulating the formation of pseudoendothelium in the spiral arteries between the 12th and 20th weeks of embryonic development [49]. Several factors are believed to interfere with this process, such as oxygen tension, and the activation of decidual NK cells and macrophages, for instance. Nonetheless, shifting the balance in the expression of angiogenic and antiangiogenic factors seems to be the key factor in the endothelial dysfunction observed in PE [22], [49], [50].
According to the literature, VEGF, PlGF, endoglin, basic fibroblast growth factor, angiopoietins, and transforming growth factor-β (TGF-β) are some angiogenic factors associated with the development of the extensive vascular network [17], [49]; and the first three factors are particularly relevant to the etiopathogenesis of PE.
VEGF is a cytokine synthesized by macrophages, T cells, tumor cells, and cytotrophoblasts [51] and, thus, it is involved in various physiological and pathological conditions [5]. VEGF isoforms include VEGF-A, VEGF-B, VEGF-C, VEGF-D and PlGF. Moreover, cells can express three main types of cellular receptors known as Flt-1 (fms-like tyrosine kinase receptor or VEGFR1), Flk-1 (kinase insert domain receptor or VEGFR2) and Flt-4 (VEGFR3), and they all have an extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain; as well as the soluble form of Flt-1 (sFlt-1), in which transmembrane and cytoplasmic domains are absent. In syncytiotrophoblast, sFlt-1 is synthesized through a splicing of mRNA of VEGRF-1 (or Flt-1) gene, which encodes proteins without the ability to bind to the VEGF or PlGF within cells, but capable of interacting with free growth factors in maternal circulation [13], [52], [53], [54]. VEGF-A, -B and PlGF bind to Flt-1; VEGF-A and -C bind to Flk-1; whereas VEGF-C and -D bind to Flt-4. Furthermore, VEGF-A, VEGF-B and PlGF may also bind to sFlt-1 [5], [49], [54], [55], [56].