Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

María F Rozas-Villanueva,Mauricio A Retamal,Paola Casanello

doi:10.3390/ijms21134698

Abstract

Preeclampsia is a pregnancy complication that appears after 20 weeks of gestation and is characterized by hypertension and proteinuria, affecting both mother and offspring. The cellular and molecular mechanisms that cause the development of preeclampsia are poorly understood. An important feature of preeclampsia is an increase in oxygen and nitrogen derived free radicals (reactive oxygen species/reactive nitrogen species (ROS/RNS), which seem to be central players setting the development and progression of preeclampsia. Cell-to-cell communication may be disrupted as well. Connexins (Cxs), a family of transmembrane proteins that form hemichannels and gap junction channels (GJCs), are essential in paracrine and autocrine cell communication, allowing the movement of signaling molecules between cells as well as between the cytoplasm and the extracellular media. GJCs and hemichannels are fundamental for communication between endothelial and smooth muscle cells and, therefore, in the control of vascular contraction and relaxation. In systemic vasculature, the activity of GJCs and hemichannels is modulated by ROS and RNS. Cxs participate in the development of the placenta and are expressed in placental vasculature. However, it is unknown whether Cxs are modulated by ROS/RNS in the placenta, or whether this potential modulation contributes to the pathogenesis of preeclampsia. Our review addresses the possible role of Cxs in preeclampsia, and the plausible modulation of Cxs-formed channels by ROS and RNS. We suggest these factors may contribute to the development of preeclampsia.

Highlights

Preeclampsia (PE) is a multisystemic disease of pregnancy, characterized by hypertension and proteinuria after 20 weeks of gestation [1]
The main theory is based on a two-stage event: First, an inefficient invasion of the spiral arteries’ walls by the extravillous trophoblast during placentation, which leads to incomplete degradation of the muscle layer of the arterial wall, and to high resistance and low flow of the placental vascular bed, generating a decreased uteroplacental perfusion
gap junction channel (GJC) and hemichannels formed by Cxs, communicate and coordinate chemical and electrical signals involved in the contraction and relaxation of the vessels through protein–protein interactions and facilitating the diffusion of vasoactive molecules

Summary

Introduction

Preeclampsia (PE) is a multisystemic disease of pregnancy, characterized by hypertension and proteinuria after 20 weeks of gestation [1]. PE is associated with several complications, such as hypertensive encephalopathy, eclampsia, renal and liver failure, pulmonary edema, coagulopathies, and uteroplacental dysfunction that may lead to intrauterine growth restriction [5]. PE may exert its consequences weeks or years after pregnancy, in the form of cardiovascular risk and postpartum depression [7], chronic hypertension, metabolic syndrome, and cardiac structural changes leading to diastolic dysfunction [8]. The uteroplacental ischemia leads to hypoxia and necrotic damage of the trophoblast, which releases soluble factors such as fms-like tyrosine kinase 1 (sFLT1) and endoglin (sENG) and other inflammatory molecules, leading to endothelial dysfunction and its effects on maternal and fetal systemic disease [6,9,10]. Further research is necessary to advance our understanding of the molecular mechanisms for PE and its sequels

Inflammation and Redox Imbalance in Preeclampsia

Hemichannels

The Role of Hemichannels and GJCs in the Vasculature

Role of Cx-Based Channels in the Placenta

Conclusions and Future Directions