The role of angiogenic factors in physiological pregnancy and pregnancy disorders - A review of the literature.

Proper placental angiogenesis is essential for fetal growth and maternal well-being during pregnancy. Imbalance between pro-angiogenic (placental growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A)) and anti-angiogenic (soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng)) factors underlies preeclampsia (PE), fetal growth restriction (FGR), and related complications. The primary scientific aim of this review is to comprehensively synthesize current evidence on the physiological mechanisms of placental angiogenesis, with a focus on VEGF/PlGF and endothelial nitric oxide synthase-nitric oxide (eNOS-NO) pathways, and to evaluate the diagnostic and predictive utility of the sFlt-1/PlGF ratio in placenta-related disorders (PE, FGR, intrauterine fetal demise, preterm birth). A secondary aim is to assess the clinical integration of angiogenic biomarkers into risk stratification and management algorithms according to international guidelines. Narrative review of literature from PubMed, Scopus, and Web of Science (2015-2025). Search terms: "placental angiogenesis", "VEGF", "PlGF", "sFlt-1", "sFlt-1/PlGF ratio", "preeclampsia", "fetal growth restriction", "spiral artery remodeling", "endothelial dysfunction". Key references were PROGNOSIS study (64) and two-stage model (2) and VEGF pathway (13). In normal pregnancy, PlGF enhances VEGF-A signaling via VEGFR-1, promoting spiral artery remodeling and villous angiogenesis. In PE and FGR, placental hypoxia drives sFlt-1 overexpression, reducing free PlGF and VEGF, leading to endothelial dysfunction. The sFlt-1/PlGF ratio<38 rules out PE within 1 week (negative predictive value [NPV] 99.3%); ratios≥85 (early-onset) and≥110 (late-onset)), predict adverse outcomes with high specificity. First-trimester screening combining PlGF with maternal factors and uterine artery Doppler detects 90% of preterm PE cases. The sFlt-1/PlGF ratio is a robust biomarker for early detection and risk stratification of PE and FGR. Repeat testing improves individualized management. Integration into clinical practice, per International Society for the Study of Hypertension in Pregnancy (ISSHP) 2021 and American College of Obstetricians and Gynecologists (ACOG) 2023 guidelines, supports timely intervention and reduces perinatal morbidity.