Adya Cherukuri

Background:  Placental insufficiency is a pathological condition in which the placenta fails to provide adequate oxygen and nutrients to support fetal development and is associated with complications such as fetal growth restriction (FGR), preeclampsia, preterm birth, and stillbirth.¹ Proper placental development depends on trophoblast invasion and spiral artery remodeling, both of which are processes supported by vascular endothelial growth factor A (VEGFA).³ During normal pregnancy, trophoblasts remodel maternal spiral arteries into low-resistance vessels capable of sustaining placental perfusion. However, persistent placental hypoxia can disrupt this process by increasing production of soluble fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor that binds and inhibits VEGFA.³ Elevated sFlt-1 and reduced VEGFA signaling have been identified as major contributors to abnormal placentation and placental dysfunction.⁵

Objective:  In this narrative review, we explored the mechanisms by which hypoxia-induced sFlt-1 overexpression suppresses VEGFA signaling, impairs trophoblast invasion and vascular remodeling, and contributes to placental insufficiency.

Search Methods: An online literature search was conducted using PubMed and Google Scholar databases from 2022 to 2025 using the following keywords: “placental insufficiency,” “sFlt-1,” “VEGFA,” “trophoblast invasion,” “hypoxia,” “spiral artery remodeling,” and “preeclampsia.”

Results:  Studies indicate that angiogenic imbalance characterized by elevated sFlt-1 and reduced VEGFA signaling is a central feature of placental dysfunction.⁵ Low-oxygen conditions in trophoblast-derived syncytiotrophoblasts significantly increased sFlt-1 secretion through hypoxia-inducible signaling pathways.³ Increased sFlt-1 expression was associated with reduced VEGFA activity, impaired trophoblast migration and invasion, and disrupted spiral artery remodeling.⁴ Experimental overexpression of placental sFLT1 in transgenic mice induced placental dysfunction characterized by abnormal morphology, altered vascularization, hypoxia, inflammation, and fetal growth restriction.¹ Reduced uterine perfusion models additionally demonstrated failed placental vascular remodeling in placental insufficiency.² Clinical literature further identified placental insufficiency as a major contributor to fetal growth restriction and adverse neonatal outcomes.⁶

Conclusions:  Current evidence supports a mechanistic pathway in which persistent placental hypoxia stimulates excess sFlt-1 production, suppresses VEGFA signaling, impairs trophoblast invasion and vascular remodeling, and ultimately contributes to placental insufficiency. These findings suggest that sFlt-1 functions not only as a biomarker of placental disease but also as an active contributor to disease progression. Improved understanding of this pathway may support earlier diagnosis, more effective biomarker interpretation, and development of targeted therapies for placental dysfunction.

Works Cited:

1. Vogtmann R, Riedel A, Sassmannshausen I, Langer S, Kühnel-Terjung E, Kimmig R, Schorle H, Winterhager E, Gellhaus A. Overexpression of human sFLT1 in the spongiotrophoblast is sufficient to induce placental dysfunction and fetal growth restriction in transgenic mice. Int J Mol Sci. 2024;25(4):2040. doi:10.3390/ijms25042040
2. van Kammen R, et al. Impaired placental vascular remodeling and persistent uterine NK cells in a rat model of reduced uterine perfusion pressure. Placenta. 2025.
3. Sasagawa T, Shibuya M. Hypoxia enhances sFLT1 secretion in human trophoblast stem cell–derived syncytiotrophoblasts. J Reprod Dev. 2025.
4. Tan HW, et al. Placental trophoblast-specific overexpression of chemerin impairs trophoblast invasion via sFlt-1 upregulation. Clin Sci (Lond). 2022;136(4):257–272.
5. Papapanagiotou A, et al. The role of angiogenetic factors in preeclampsia. Int J Mol Sci. 2025;26(21):10431. doi:10.3390/ijms262110431
6. Tsikouras P, Antsaklis P, Nikolettos K, Kotanidou S, Kritsotaki N, Bothou A, Andreou S, Nalmpanti T, Chalkia K, Spanakis V, Iatrakis G, Nikolettos N. Diagnosis, Prevention, and Management of Fetal Growth Restriction (FGR). J Pers Med. 2024 Jun 28;14(7):698. doi: 10.3390/jpm14070698. PMID: 39063953; PMCID: PMC11278205.