title: Placental-specific sFLT-1: role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis.
abstract: Pre-eclampsia is a common obstetric complication globally responsible for a significant burden of maternal and perinatal morbidity and mortality. Central to its pathophysiology is the anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1). sFLT-1 is released from a range of tissues into the circulation, where it antagonizes the activity of vascular endothelial growth factor and placental growth factor leading to endothelial dysfunction. It is this widespread endothelial dysfunction that produces the clinical features of pre-eclampsia including hypertension and proteinuria. There are multiple splice variants of sFLT-1. One, known as sFLT-1 e15a, evolved quite recently and is only present in humans and higher order primates. This sFLT-1 variant is also the main sFLT-1 secreted from the placenta. Recent work has shown that sFLT-1 e15a is significantly elevated in the placenta and circulation of women with pre-eclampsia. It is also biologically active, capable of causing endothelial dysfunction and the end-organ dysfunction seen in pre-eclampsia. Indeed, the over-expression of sFLT-1 e15a in mice recapitulates the pre-eclamptic phenotype in pregnancy. Therefore, here we propose that sFLT-1 e15a may be the sFLT-1 variant primarily responsible for pre-eclampsia, a uniquely human disease. Furthermore, this placental-specific sFLT-1 variant provides promise for use as an accurate biomarker in the prediction or diagnosis of pre-eclampsia.
authors.affiliation: Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton, 3168 Victoria, Australia.|Translational Obstetric Group, University of Melbourne, Mercy Hospital for Women, 163 Studley Rd, Heidelberg, 3084 Victoria, Australia.
authors.forename: K R
authors.initials: KR
authors.lastname: Palmer
authors.affiliation: Translational Obstetric Group, University of Melbourne, Mercy Hospital for Women, 163 Studley Rd, Heidelberg, 3084 Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Tong
authors.affiliation: Translational Obstetric Group, University of Melbourne, Mercy Hospital for Women, 163 Studley Rd, Heidelberg, 3084 Victoria, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010920:Placenta / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D000072483:Placenta Growth Factor / Q000235:genetics / Q000378:metabolism; D011225:Pre-Eclampsia / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; C000608036:PGF protein, human; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: VEGF; anti-angiogenic factors; hypoxia; placenta; pre-eclampsia; sFLT-1; splice variant