Pathophysiological roles of ADMA-mediated endothelial injury in hypertensive disorders of pregnancy

Abstract

Hypertensive disorders of pregnancy (HDP) represent a major cause of maternal and neonatal morbidity and mortality. Studies conducted over the last decade have improved our understanding of the potential mechanisms underlying HDP pathogenesis. The first step in HDP is reduced uteroplacental perfusion as a result of abnormal extravillous trophoblast invasion of spiral arterioles. Subsequent placental ischemia leads to maternal vascular endothelial dysfunction that may be caused by an imbalance between pro- and anti-angiogenic factors, enhanced formation of vasocontractile factors such as endothelin and thromboxane, increased vascular sensitivity to angiotensin II, and/or decreased formation of vasodilators such as nitric oxide (NO) and prostaglandin I2. NO is one of the major mediators from the endothelium, and its production is modified by endogenous NO synthase inhibitors such as asymmetric dimethylarginine (ADMA). ADMA levels are generally higher in patients with cardiovascular and metabolic diseases and widely recognized as a prognostic marker for major cardiovascular events and mortality. Recent studies have found ADMA levels to be higher in patients with preeclampsia. In addition, multiple studies indicate that elevated ADMA in early stages of pregnancy might predict the development of preeclampsia. Finally, ADMA has been found to be associated with uterine artery flow disturbance. Collectively, these findings strongly suggest that elevated ADMA-mediated endothelial dysfunction could be a causative factor for HDP. In this review, we discuss the biology of ADMA, with a particular focus on its potential role in HDP.