Beyond the Biomarkers: Gestation-Dependent Roles of sFLT-1 and PlGF in Human and Non-Human Mammalian Placental Development and Function.

Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT-1) are established biomarkers of placental dysfunction, but their functions extend beyond the maternal circulating ratio. This structured narrative review examines the FLT1-PlGF-vascular endothelial growth factor system across implantation, trophoblast differentiation, uterine vascular transformation, foetoplacental angiogenesis, exchange capacity development and late-gestational maturation. Human evidence is integrated with selected non-human mammalian studies according to gestational stage, cellular source, anatomical compartment, molecular isoform and placental architecture. We use a compartmentalised angiogenic rheostat as a qualitative organising framework, not an experimentally validated model. It integrates established ligand-receptor biology with human observations and experimental perturbations: PlGF modifies FLT1 signalling and VEGF-A availability, whereas membrane and soluble FLT1 influence ligand distribution and vascular responses. Experimental evidence supports physiological ligand restraint and the pathogenic effects of excessive sFLT-1; human associations do not invariably establish the initiating placental lesion. Pre-eclampsia, foetal growth restriction and invasive placentation illustrate distinct contexts in which angiogenic regulation may become maladaptive. The maternal sFLT-1/PlGF ratio is therefore interpreted as a circulating indicator of placental vascular stress rather than a direct measurement of local signalling.