Endothelial dysfunction and preeclampsia: role of oxidative stress

Abstract

Preeclampsia (PE) is an often fatal pathology characterized by hypertension and proteinuria at the 20th week of gestation that affects 5-10% of the pregnancies. The problem is particularly important in developing countries in where the incidence of hypertensive disorders of pregnancy is higher and maternal mortality rates are 20 times higher than those reported in developed countries. Risk factors for the development of PE include obesity, insulin resistance and hyperlipidemia that stimulate inflammatory cytokine release and oxidative stress leading to endothelial dysfunction (ED). However, how all these clinical manifestations concur to develop PE is still not very well understood. The related poor trophoblast invasion and uteroplacental artery remodeling described in PE, increases reactive oxygen species (ROS), hypoxia and ED. Here we aim to review current literature from research showing the interplay between oxidative stress, ED and PE to the outcomes of current clinical trials aiming to prevent PE with antioxidant supplementation.

Keywords: endothelial dysfunction; oxidative stress; preeclampsia; reactive oxygen species; superoxide.

Figure 1

Mechanisms of endothelial dysfunction in preeclampsia. Poor trophoblast invasion in PE causes impaired spiral artery remodeling following by placental ischemia/reperfusion and inflammation. Within the trophoblast cell, oxidative stress from unbalanced free radical formation is formed from different sources like XO, eNOS uncoupling, NADPH oxidase, and mitochondria. Ultimately, the reunion of all these events lead to peroxynitrite formation, lipid peroxidation, protein modification, MMP activation and DNA damage, contributing to endothelial dysfunction.

Figure 2

Role of anti-angiogenic factor sFlt-1 in preeclampsia. (A) Flt-1 (light blue) and Flk-1 (yellow), are VEGF receptor tyrosine kinases that regulate the process of angiogenesis and vasculogenesis, among other events in cells in PE. Soluble form of VEGF receptor 1, sFlt-1 under normal conditions regulates VEGF levels, angiogenesis and vasculogenesis. (B) Under hypoxic conditions, Flt-1 is cleaved producing sFlt-1 in high concentrations. sFlt-1 then competes with Flt-1 for binding of VEGF-A and PlGF causing an impairment in the angiogenesis process by decreasing the bioavailability of VEGF-A and PlGF to Flt-1 and Flk-1.