Placental ischemia and cardiovascular dysfunction in preeclampsia and beyond: making the connections

Abstract

Hypertensive disorders of pregnancy continue to be a significant source of maternal and fetal morbidity and mortality, and recent evidence suggests that the incidence of preeclampsia (PE) is increasing. Recent epidemiological studies indicate that the effects of PE may persist long after pregnancy, in both the mother and the offspring, as increased incidence of cardiovascular disease. The last decade has produced new insights into the pathogenesis of PE. The initiating event in PE appears to be impaired placental perfusion and subsequent placental ischemia, which results in the elaboration of numerous factors. Factors such as soluble fms-like tyrosine kinase-1, soluble endoglin and the angiotensin II type-1 receptor autoantibodies contribute to maternal endothelial and cardiovascular dysfunction, marked by increased reactive oxygen species and decreased bioavailable VEGF, nitric oxide and prostacyclin. However, the importance of the various endothelial and humoral factors that mediate these changes during PE remain to be elucidated.

Figure 1. Pathways by which placental ischemia may lead to endothelial and cardiovascular dysfunction during and after pregnancy

Placental ischemia results in increased synthesis of factors such as soluble fms-like tyrosine kinase-1 and various inflammatory cytokines, which in turn result in endothelial dysfunction and ultimately hypertension. Once hypertension is established, it results in ventricular hypertrophy, renal injury and additional endothelial dysfunction, all of which could contribute to in an increased risk of CVD and/or ESRD in later life. CVD: Cardiovascular disease; ESRD: End-stage renal disease; HTN: Hypertension.

Figure 2. Pathways by which reduced uterine perfusion pressure and placental ischemia may lead to endothelial and cardiovascular dysfunction during pregnancy

Genetic and/or environmental factors may interact with insufficient placentation or inappropriate cardiovascular adaptations to result in reduced uterine perfusion and placental ischemia. Placental ischemia results in increased synthesis of HIF-1α, which increases soluble fms-like tyrosine kinase-1 and soluble endoglin. Placental ischemia also results in production of AT₁-AA. Elevations in these factors are proposed to result in endothelial dysfunction, by decreases in bioavailable nitric oxide, and increased ROS and ET-1, which in turn results in altered renal function, increased total peripheral resistance and, ultimately, hypertension. AT₁-AA: Angiotensin II type-1 receptor autoantibodies; ET: Endothelin; HIF: Hypoxia-inducible factor; ROS: Reactive oxygen species.