What is the role of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and transforming growth factor beta (TGF-β) in preeclampsia?

Role of Angiogenic and Anti-Angiogenic Factors in Preeclampsia

These biomarkers represent the central pathophysiologic mechanism of preeclampsia: the ischemic placenta releases excessive anti-angiogenic factors (sFlt-1 and sEng) that bind and neutralize pro-angiogenic factors (VEGF, PlGF, and TGF-β), creating an angiogenic imbalance that causes widespread maternal endothelial dysfunction, hypertension, proteinuria, and multi-organ damage. 1

The Two-Stage Disease Model

Preeclampsia operates through a sequential pathophysiologic cascade 1, 2:

• Stage 1 (Placental): Abnormal placentation with shallow cytotrophoblast invasion and defective spiral artery remodeling leads to placental ischemia and hypoxia 3, 1
• Stage 2 (Maternal): The stressed placenta releases pathogenic factors into maternal circulation, triggering systemic endothelial dysfunction 1, 2

Soluble fms-like Tyrosine Kinase-1 (sFlt-1)

sFlt-1 is the primary anti-angiogenic mediator in preeclampsia 3:

• sFlt-1 is a circulating soluble isoform of the VEGF receptor with potent anti-angiogenic properties 3
• It acts as a decoy receptor that binds and neutralizes free VEGF and PlGF in maternal circulation 3, 1
• Circulating sFlt-1 levels are markedly increased in women with preeclampsia, with elevations beginning 5-6 weeks before clinical manifestations 4, 5
• AT1 receptor autoantibodies (present in >95% of preeclamptic women) induce placental sFlt-1 production through AT1R activation 3
• The sFlt-1/PlGF ratio serves as a validated biomarker with 74% sensitivity and 97% specificity for predicting adverse outcomes in early-onset preeclampsia 6

Vascular Endothelial Growth Factor (VEGF)

VEGF deficiency is central to endothelial dysfunction 3, 1:

• VEGF normally promotes vasodilation by increasing nitric oxide and prostacyclin production 6
• Free VEGF levels are markedly decreased in preeclampsia due to sFlt-1 binding 4, 7
• This VEGF deficiency reduces vasodilators, leading to vasoconstriction and hypertension 6
• The loss of VEGF signaling contributes to glomerular endotheliosis (the pathognomonic renal lesion), proteinuria, and decreased glomerular filtration rate 3, 6

Placental Growth Factor (PlGF)

PlGF is the key pro-angiogenic factor that becomes depleted 1, 4:

• PlGF is bound and neutralized by excess sFlt-1 in maternal circulation 3, 1
• Free PlGF levels are markedly diminished in preeclampsia, with decreases correlating inversely with sFlt-1 increases 4, 5
• The decline in PlGF begins 5-6 weeks before clinical disease onset 5
• PlGF measurement provides high negative predictive value to rule out preeclampsia requiring delivery within 7-14 days when the sFlt-1/PlGF ratio is low 6

Soluble Endoglin (sEng)

sEng amplifies the severity of preeclampsia, particularly in HELLP syndrome 8:

• sEng is a soluble TGF-β coreceptor released from the placenta that is elevated in preeclamptic sera and correlates with disease severity 8
• It inhibits capillary tube formation in vitro and induces vascular permeability and hypertension in vivo 8
• When coadministered with sFlt-1 in pregnant rats, sEng produces severe preeclampsia including HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and fetal growth restriction 8
• sEng impairs TGF-β1 binding to its receptors and downstream signaling, including effects on eNOS activation and vasodilation 8
• Higher sEng/TGF-β1 ratios are associated with preeclampsia compared to normotensive pregnancies 9

Transforming Growth Factor Beta (TGF-β)

TGF-β signaling becomes dysregulated through sEng interference 8:

• TGF-β1 and TGF-β3 are bound by sEng in maternal circulation, disrupting normal vascular signaling 8, 7
• Unlike the other factors, TGF-β1 levels remain relatively unchanged across preeclamptic and normotensive groups 9
• The critical pathology is not TGF-β deficiency per se, but rather impaired TGF-β receptor binding and downstream signaling caused by sEng 8
• This dysregulated TGF-β signaling contributes to endothelial dysfunction and impaired vasodilation 8

Clinical Implications of the Angiogenic Imbalance

The combined effect of these factors produces multi-organ maternal dysfunction 1, 6:

• Cardiovascular: Vasoconstriction, hypertension, and increased sensitivity to pressor agents 3, 6
• Renal: Glomerular endotheliosis, proteinuria, decreased GFR 3, 6
• Hepatic: Reduced perfusion causing necrosis, hemorrhage, elevated liver enzymes, and epigastric pain 6
• Cerebral: Edema leading to headache, visual disturbances, and seizures 6
• Hematologic: Hemolysis and thrombocytopenia in severe cases (HELLP syndrome) 6, 8

Diagnostic and Therapeutic Applications

The sFlt-1/PlGF ratio has become the most clinically useful biomarker 6:

• A ratio ≥85 between 20-34+6 weeks gestation can rule out preeclampsia requiring delivery within 7-14 days with high negative predictive value 6
• Automated assays for plasma, serum, and urine measurement have accelerated time to clinical diagnosis and minimized maternal adverse outcomes 4
• Dextran sulfate apheresis can reduce circulating sFlt-1 levels in early preterm preeclampsia, showing reduced proteinuria and stabilized blood pressure in pilot studies, though larger randomized trials are needed 6

Common Pitfalls to Avoid

• Do not assume that elevated sFlt-1 or low PlGF alone confirms preeclampsia—the diagnosis requires clinical criteria (hypertension plus organ dysfunction) 6
• Recognize that angiogenic factor alterations precede clinical disease by 5-6 weeks, making them useful for prediction but not immediate diagnosis 4, 5
• Understand that while hypoxia was historically considered the primary stimulus for sFlt-1 release, inflammatory mechanisms and oxidative stress play equally important roles 5, 7
• Remember that delivery of the placenta remains the only definitive treatment, as it removes the source of circulating pathogenic factors 1, 6