*3.5. sTie-2*

During development, vascular endothelial cells express the transmembrane tyrosine kinase receptors Tie-1 and Tie-2, which are responsible for vascular maturation and angiogenesis [40]. Angiopoietin-1 via Tie-2 signaling facilitates endothelial development, whilst Ang-2 acts as an Ang-1 antagonist by binding to the Tie-2 receptor [41].

However, whilst vessel growth is dependent on Tie-2 [19], Tie-2 may be proteolytically cleaved to produce sTie-2. This soluble form inhibits Tie-2 signaling by averting angiogenesis [19,20]. Mazibuko et al. (2019) demonstrated that soluble Tie-2 levels were dissimilar between preeclamptic and control pregnancies (*p* = 0.0403). In contrast, HIV status did not affect sTie2 and soluble human epidermal growth factor receptor 2 (sHER2) manifestation [42]. Also, HER2 is a membrane-bound receptor tyrosine kinase that is shed via proteolytic cleavage into body fluids [43]. Mazibuko et al. (2019) reported that sHER2 levels were similar between pregnancy types (control *vs.* PE; *p* = 0.3677), regardless of HIV status (*p* = 0.5249). These results may be due to the hypoxic pro-oxidative milieu of both PE and HIV infection, as sHER2 interferes with mitogen-activated protein kinase (MAPK) and Phosphatidylinositol-3-kinase/ protein kinase B (P13K/Akt) signaling [42].

#### *3.6. Vascular Endothelial Growth Factor and HIV Tat protein*

The accessory protein Tat of HIV-1 interferes with intracellular function by evading host response mechanisms, and may, therefore, contribute to the high inflammatory reaction in HIV-infected PE [44]. The Tat protein is a trans-activator of viral gene expression and is released extracellularly during HIV acute infection [45]. Since Tat has a similar arginine- and lysine-rich sequence to VEGF, it is recognized as a powerful angiogenic factor [46]. Tat imitates VEGF by attaching to and stimulating Flk-1/KDR [47]. Tat promotes endothelial cell adhesion through the binding of its arginine–glycine–aspartic acid region to the <sup>α</sup>vβ<sup>3</sup> and <sup>α</sup>5β1 integrins and VEGFR-2/KDR via its basic domain [46]. Also, a combined Tat/FGF-2 e ffect is attributed to fibroblast growth factor (FGF-2), which induces the expression of the <sup>α</sup>vβ<sup>3</sup> and <sup>α</sup>5β1 integrins, which aids Tat binding [48].

Additionally, HIV-1 via gp120 binds to heparin sulphate proteoglycans (HSPG) on endothelial cells, amplifying viral infectivity and thereby expediting the release of Tat [49]. Tat induces endothelial cells to migrate, adhere, and grow as a capillary-like network in vitro [50]. HIV Tat was also shown to bind F1k-1/KDR, one of the receptors for VEGF, suggesting an additional mechanism for Tat to exert its angiogenic e ffect [47].

Defective cell signaling by the Tat protein alters endothelial cell morphology, gene expression, and survival by stimulating the MAPK pathway. The movement from the gap 0 to gap 1 (G0 to G1) phase of naïve T cells enables productive HIV infection [51]. The HIV-1 Tat protein facilitates MAPK activity by promoting a change from the G0 to G1 phase of naïve T cells, thereby stimulating HIV infection [51].
