Preeclampsia: Maternal Systemic Vascular Disorder Caused by Generalized Endothelial Dysfunction Due to Placental Antiangiogenic Factors

Abstract

Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries.

Keywords: angiogenic imbalance; arterial stiffness; endothelial dysfunction; placental growth factor; preeclampsia; soluble fms-like tyrosine kinase 1; systemic vascular dysfunction; vascular endothelial growth factor.

Figure 1

Two-stage theory of the pathophysiology of preeclampsia. Predisposing immunological, genetic, and preexisting maternal risk factors may affect abnormal cytotrophoblast invasion of spiral arteries (abnormal placentation) (First stage). The reduced uteroplacental perfusion induces placental release of antiangiogenic factors (soluble fms-like tyrosine kinase 1 (sFlt1)) into the maternal circulation, which antagonizes proangiogenic factors, leading to endothelial dysfunction and systemic vascular dysfunction (Second stage). Preexisting maternal conditions such as chronic hypertension, systemic lupus erythematosus (SLE), and obesity is also associated with endothelial dysfunction.

Figure 2

Mechanisms of endothelial dysfunction leading to systemic vascular dysfunction in preeclampsia. Excessive soluble fms-like tyrosine kinase 1 (sFlt1) antagonizes VEGF or PlGF, or both, and causes endothelial dysfunction, including a decrease in vasodilators such as nitric oxide (NO) and prostacyclin (PGI₂) and an increase in vasoconstrictors such as endothelin-1 (ET-1). VEGF: vascular endothelial growth factor; PLGF: placental growth factor; VEGFR1: VEGF receptor 1 (also known as Flt1).