Placental malaria and VEGF modulation by P. falciparum: Bridging the immunopathological gap using evidence from human cerebral and severe, non-cerebral malaria studies.

Malaria, primarily caused by Plasmodium falciparum (Pf), remains a significant public health concern in Southeast Asia and sub-Saharan Africa, disproportionately affecting pregnant women, leading to adverse maternal and fetal outcomes. Placental malaria (PM) is characterized by sequestration of P. falciparum infected erythrocytes in intervillous space, which causes activation of immune response at maternal-fetal interface and altered expression of angiogenic regulators like VEGF, sVEGFR1, Angiopoietins (ANG), sEndoglin, and placental growth factor (PLGF). Emerging evidence suggests that the late stages of P. falciparum, internalize the vascular endothelial growth factor (VEGF) of the host and express VEGF receptors (primarily activated VEGFR2) on the surface of parasitized red blood cells (PRBCs). These mechanisms were mainly explored using immunohistochemistry and immunocytochemistry-based studies of fatal cerebral and severe non-cerebral malaria cases and in an in-vitro culture using the 3D7 strain of P. falciparum but remain largely unexplored in PM. Disrupted VEGF signaling, dysregulated levels of other angiogenic factors, altered cytokines/chemokines signaling and increased oxidative stress may lead to placental insufficiency, fetal growth restriction, and preeclampsia. Quantitative plasma VEGF, VEGFR1, VEGFR2 and comparative immunohistochemistry and immunocytochemistry-based studies are needed to elucidate VEGF dynamics in PM from different endemic areas.