Angiogenic Imbalance in Early Placental Dysfunction: Pro- and Anti-Angiogenic Factors, Pathophysiology, Screening and Therapeutic Horizons

Placental dysfunction is a major component of several pregnancy complications, particularly preeclampsia and fetal growth restriction (FGR). These disorders could be presented with different phenotypes based on abnormal placentation and inadequate maternal vascular adaptation, which are baseline mechanisms in affected pregnancies. Defective trophoblast invasion and incomplete transformation of the maternal spiral arteries may produce a high-resistance uteroplacental circulation, resulting in placental hypo-perfusion, ischemia–reperfusion injury, oxidative stress and subsequent release of factors that affect maternal endothelial function. The aim of this review is to summarize the current understanding of pro-angiogenic and anti-angiogenic factors in early placental dysfunction, with special emphasis in their biological function and molecular roles, relationship with abnormal placentation and clinical significance during pregnancy. The development of placental dysfunction is generally understood as a multifactorial and multistep process. The literature evidence most often supports the three-step process of placenta dysfunction. The angiogenic imbalance may precede the clinical presentation of preeclampsia and may also be associated with fetal growth restriction. Among currently available biomarkers, the sFlt-1/PlGF ratio has the strongest clinical evidence for risk stratification in women with suspected preeclampsia. Nevertheless, the role of angiogenic factors in the earliest stages of placental dysfunction remains incompletely defined. The major challenge is to determine whether angiogenic abnormalities can identify clinically meaningful placental dysfunction early enough to permit effective intervention. This suggests that pro-angiogenic therapeutics could be a possible option for the treatment of pre-eclampsia, but also a more specific and sensitive predictive and diagnostic tool in modern obstetrics.