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Trophoblast invasion and spiral artery remodeling: a molecular framework for preeclampsia
Preeclampsia (PE) remains a leading cause of maternal and perinatal morbidity and mortality, yet its pathogenesis is not fully understood. Impaired invasion of extravillous trophoblasts (EVTs) and defective spiral artery remodeling are particularly associated with early-onset PE, defined by clinical onset before 34 weeks of gestation. In late-onset PE, presenting at or after 34 weeks, placental stress may interact with maternal cardiovascular and metabolic susceptibility, resulting in substantial mechanistic overlap between the two phenotypes. This review summarizes the molecular regulation of EVT differentiation, proliferation, migration, and invasion, with a focus on mechanisms of abnormal placentation particularly relevant to early-onset PE. We discuss key signaling pathways, including PI3K/AKT/mTOR, Wnt, MAPK/ERK, JAK/STAT, Notch, and TGF-β, which coordinate epithelial–mesenchymal transition (EMT), integrin switching, MMP-2/MMP-9 secretion, and invadopodia formation. As invasion proceeds, EVTs undergo pseudo-endothelialization, acquiring endothelial markers such as VE-cadherin, PECAM-1, and VCAM-1 and inducing FasL/TRAIL-mediated apoptosis of maternal endothelial cells. Defects at any of these stages, from persistence of a proliferative, non-invasive phenotype to incomplete EMT and pseudovasculogenesis, may impair spiral artery remodeling in PE. Decidual immune cells, including uterine natural killer cells, macrophages, and regulatory T cells, also regulate EVT invasion through KIR–HLA interactions, cytokine networks, and PD-1/PD-L1 signaling. Enhanced pro-inflammatory signaling and weakened immune tolerance may therefore contribute to disease progression. Metabolic disturbances provide an additional regulatory layer: altered lipoprotein concentrations and composition, oxidized low-density lipoprotein, saturated fatty acids, impaired cholesterol homeostasis, and lipid peroxidation may restrict trophoblast invasion, promote antiangiogenic signaling, and aggravate endothelial dysfunction. These interconnected mechanisms identify several therapeutic targets, although current treatment options remain limited. Approaches under investigation include restoring angiogenic balance through placental growth factor supplementation or removal of soluble fms-like tyrosine kinase 1, modulating PI3K/AKT signaling, using nutraceuticals, and developing placenta-targeted delivery systems. Abnormalities in EVT function, vascular remodeling, immune regulation, and lipid metabolism may contribute to PE, but their relative importance varies across disease phenotypes. Therefore, their relevance to early- and late-onset PE should be evaluated separately, and potential preventive and therapeutic strategies should account for disease subtype, gestational timing, and maternal and fetal safety.