The Roles of Obesity and ASB4 in Preeclampsia Pathogenesis

Abstract

Preeclampsia is a complex pregnancy-related hypertensive disorder which poses significant risks for both maternal and fetal health. Preeclampsia affects 5-8% of pregnancies in the United States, causing a significant public health and economic burden. Despite extensive research, the etiology and pathogenesis of preeclampsia remain elusive, but have been correlated with maternal conditions such as obesity. In recent decades, the incidence of preeclampsia increased along with the prevalence of obesity among women of reproductive age. Maternal obesity has been shown to negatively affect pregnancy in almost all aspects. However, the precise mechanisms by which obesity influences preeclampsia are unclear. Ankyrin repeat and SOCS Box Containing protein 4 (ASB4) is an E3 ubiquitin ligase that can promote the degradation of a wide range of target proteins. ASB4-null mice display a full spectrum of preeclampsia-like phenotypes during pregnancy including hypertension, proteinuria, and decreased litter size. Furthermore, maternal obesity induced by a high-fat diet aggravates preeclampsia-like phenotypes in pregnant mice lacking ASB4. Variants in the ASB4 gene have been associated with obesity in humans, and a functional connection between the ASB4 gene and obesity has been established in mice. This review discusses the connections between preeclampsia, obesity, and ASB4.

Keywords: ASB4; endometrium; implantation; insulin; leptin; obesity; preeclampsia; trophoblast.

Figure 1

Defects during trophoblast invasion cause the shallow remodeling of uteroplacental spiral arteries. Abnormal vascular remodeling contributes to poor placentation due to the reduction in placental perfusion, making the placenta hypoxic/ischemic. The abnormal placenta releases inflammatory cytokines, anti-angiogenic factors, and reactive oxygen species into systemic circulation. These factors subsequently cause systemic endothelial dysfunction, leading to the clinical manifestations of preeclampsia (end-organ damage, proteinuria, and hypertension). “↓” denotes causation. All images are created with BioRender.com.

Figure 2

A graphical overview of how maternal obesity caused by excessive adipose tissue (denoted as yellowish spheres around the abdominal area of the pregnant mother) contributes to the pathogenesis of preeclampsia. All images are created with BioRender.com.