A Narrative Review on the Pathophysiology of Preeclampsia

Abstract

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia's effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies.

Keywords: abnormal placentation; endothelial dysfunction; oxidative stress; pathophysiology; preeclampsia; systemic inflammation.

Figure 1

Hypotheses on the etiology of preeclampsia. The two-stage hypothesis suggests the condition develops from impaired placentation followed by a maternal systemic response. The genetic and epigenetic hypothesis focuses on genetic predispositions and epigenetic changes. The immunological hypothesis proposes abnormal maternal immune adaptation. The angiogenic imbalance hypothesis highlights the imbalance between pro-angiogenic and anti-angiogenic factors. The placental hypoxia and oxidative stress hypothesis emphasizes oxidative stress from placental hypoxia. Other contributing factors include metabolic syndrome, environmental agents, hormonal imbalances, maternal infections, intestinal dysbiosis, sleep disorders, fetal conditions, autoimmune disorders, endocrine disorders, and placental aging.

Figure 2

Mechanisms of abnormal placentation in preeclampsia. (1) Early in pregnancy, trophoblast cells invade the maternal decidua to establish a connection between maternal blood supply and the developing fetus. (2) In a healthy pregnancy, extravillous trophoblasts invade the maternal spiral arteries, transforming these high-resistance vessels into low-resistance channels, ensuring adequate blood flow to the placenta and fetus. (3) A balanced immune response is vital. Dysfunctional interactions between immune cells and trophoblasts in preeclampsia lead to inadequate spiral artery remodeling. (4) In preeclampsia, the invasion of trophoblasts is shallow, failing to reach the deeper segments of the spiral arteries. This leads to increased resistance and reduced blood flow to the placenta. (5) The inadequate remodeling creates a hypoxic and ischemic environment within the placenta, stimulating the release of pro-inflammatory and anti-angiogenic factors, leading to systemic endothelial dysfunction. (6) In preeclampsia, excess SDEVs carry bioactive molecules that induce inflammation, endothelial dysfunction, and coagulation abnormalities, exacerbating systemic endothelial dysfunction.

Figure 3

Maternal systemic response in preeclampsia. Genetic factors include polymorphisms in genes such as soluble fms-like tyrosine kinase-1 (sFlt-1), nitric oxide synthase 3 (NOS3), and guanylate cyclase 1 soluble subunit alpha 3 (GUCY1A3), which affect angiogenesis and nitric oxide bioavailability, contributing to endothelial dysfunction. Hypoxia and oxidative stress result from abnormal placentation, leading to reactive oxygen species production and endothelial damage. Epigenetic factors involve hypomethylation of the methylenetetrahydrofolate reductase (MTHFR) gene promoter and polymorphisms in genes like complement component 3 (C3) and tumor necrosis factor-alpha (TNF-α), contributing to inflammation. Placental hypoxia triggers the release of anti-angiogenic factors such as soluble endoglin (sEng) and sFlt-1, disrupting endothelial repair. Ferroptosis exacerbates oxidative stress through iron-dependent cell death. Endothelial dysfunction is marked by increased permeability and inflammatory cytokines. Additional factors include mitochondrial dysfunction, platelet activation, adipokines, and systemic inflammation involving elevated cytokines like interleukin-6 (IL-6), TNF-α, and reactive oxygen species (ROS), perpetuating endothelial damage and oxidative stress.