{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:55:43Z","timestamp":1791291343335,"version":"4.3.0"},"reference-count":77,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013PlGF\u2013vascular 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\u2013receptor 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.<\/jats:p>","DOI":"10.3390\/cells15191817","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:13:12Z","timestamp":1791288792000},"page":"1817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond the Biomarkers: Gestation-Dependent Roles of sFLT-1 and PlGF in Human and Non-Human Mammalian Placental Development and Function"],"prefix":"10.3390","volume":"15","author":[{"given":"Zoe","family":"Byrne","sequence":"first","affiliation":[{"name":"Maternal Fetal Medicine Unit, Obstetrics & Gynaecology Department, Townsville Hospital and Health Service, 100 Angus Smith Drive, Douglas, Townsville, QLD 4810, Australia"},{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4810, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Brennan","sequence":"additional","affiliation":[{"name":"Maternal Fetal Medicine Unit, Obstetrics & Gynaecology Department, Townsville Hospital and Health Service, 100 Angus Smith Drive, Douglas, Townsville, QLD 4810, Australia"},{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4810, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Watson","sequence":"additional","affiliation":[{"name":"Maternal Fetal Medicine Unit, Obstetrics & Gynaecology Department, Townsville Hospital and Health Service, 100 Angus Smith Drive, Douglas, Townsville, QLD 4810, Australia"},{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4810, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4895-1791","authenticated-orcid":false,"given":"Donna","family":"Rudd","sequence":"additional","affiliation":[{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4810, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoga","family":"Kandasamy","sequence":"additional","affiliation":[{"name":"College of Medicine and Dentistry, James Cook University, Townsville, QLD 4810, Australia"},{"name":"Neonatal Intensive Care Unit, Townsville Hospital and Health Service, Townsville, QLD 4810, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Failla, C.M., Carbone, M.L., Ramondino, C., Bruni, E., and Orecchia, A. 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