*4.2. Lymphangiogenesis and Preeclampsia*

In PE, a dysfunctional fluid clearance manifests as an excessive accumulation of interstitial fluid causing edema [74]. B cells, macrophages, and reticular stromal cells activate the production of VEGF A, C, and D, thereby affecting signaling pathways for the induction of lymphangiogenesis [74]. Increased lymphangiogenesis (pro VEGF-C) is a compensatory response to the heightened exaggerated inflammatory state of PE [75,76]. Indeed, VEGFinduceslymphangiogenesis [65]. Nevertheless, Shange et al. (2017) reported no significant difference between VEGF-C and D from PE mothers and control [74]. This upregulation of VEGF-C in PE was observed in early-onset PE; however, one needs to note that patients were on dual ARV therapy [73].

Furthermore, hypoxia-inducible factor-1 (HIF-1) plays an important role in the pathogenesis of PE, and indirectly enhances the molecular regulation of VEGF [66,67,77]. The upregulated *HIF-1* gene plays a critical role in the pathogenesis of PE [58,78–80] and contributes to the lymphangiogenesis in PE.
