Vascular Dysfunction in Preeclampsia LESLEY J. BRENNAN,* ,† JUDE S. MORTON,* ,† AND SANDRA T. DAVIDGE* ,†,‡ *Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, Alberta, Canada; † Women and Children’s Health Research Institute and the Cardiovascular Research Centre, Edmonton, Alberta, Canada; ‡ Department of Physiology, University of Alberta, Edmonton, Alberta, Canada Address for correspondence: Dr. Sandra T. Davidge, Ph.D., Departments of Obstetrics/Gynaecology and Physiology, 232 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail: sandra.davidge@ualberta.ca Received 2 May 2013; accepted 22 July 2013. ABSTRACT Preeclampsia is a complex disorder which affects an estimated 5% of all pregnancies worldwide. It is diagnosed by hypertension in the presence of proteinuria after the 20th week of pregnancy and is a prominent cause of maternal morbidity and mortality. As delivery is currently the only known treatment, preeclampsia is also a leading cause of preterm delivery. Preeclampsia is associated with maternal vascular dysfunction, leading to serious cardiovascular risk both during and following pregnancy. Endothelial dysfunction, resulting in increased peripheral resistance, is an integral part of the maternal syndrome. While the cause of preeclampsia remains unknown, placental ischemia resulting from aberrant placentation is a fundamental characteristic of the disorder. Poor placentation is believed to stimulate the release of a number of factors including pro- and antiangiogenic factors and inflammatory activators into the maternal systemic circulation. These factors are critical medi- ators of vascular function and impact the endothelium in distinctive ways, including enhanced endothelial oxidative stress. The mecha- nisms of action and the consequences on the maternal vasculature will be discussed in this review. KEY WORDS: preeclampsia, endothelial dysfunction, placental ische- mia, circulating factors Abbreviations used: ADMA, asymmetric dimethylarginine; AT 1 - AA, agonistic autoantibodies to the angiotensin II type I receptor; bET-1, big endothelin-1; CACs, circulating angiogenic cells; CVD, cardiovascular disease; ECFCs, endothelial colony forming cells; EDH, endothelium-dependent hyperpolarization; eNOS, endothelial nitric oxide synthase; EPCs, endothelial progenitor cells; ERPF, effective renal plasma flow; ET-1, endothelin-1; GFR, glomerular filtration rate; H 2 O 2 , hydrogen peroxide; HELLP, hemolysis, elevated liver enzymes, and low platelets; HIF-1, hypoxia-inducible factor-1; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; LOX-1, lectin-like oxidized LDL receptor-1; MCP-1, monocyte chemoattractant protein-1; MEGJs, myoendothelial gap junctions; NAD(P)H oxidase, nicotinamide adenine dinucleotide phosphate- oxidase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK, natural killer; NO, nitric oxide; Nrp-1, neuropilin-1; O 2 Á-, superoxide; OH, hydroxyl radical; ONOO À , peroxynitrite; oxLDL, oxidized low-density lipoprotein; Pai-1, plasminogen activator inhibitor type 1; PARP, poly(ADP-ribose) polymerase; PCAM-1, platelet endothelial cell adhesion molecule-1; PDGF, platelet-derived growth factor; PIGF, placental growth factor; RNS, reactive nitrogen species; ROS, reactive oxygen species; RUPP, reduced uteroplacental perfusion; sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase 1; TGF, transforming growth factor; TNF-a, tumor necrosis factor-alpha; VCAM-1, vascular cell adhe- sion molecule-1; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cells. Please cite this paper as: Brennan LJ, Morton JS, Davidge ST. Vascular dysfunction in preeclampsia. Microcirculation 21: 4–14, 2014. INTRODUCTION Preeclampsia is a multifaceted disorder of human pregnancy which affects millions of women worldwide (approximately 5% of all pregnancies) each year (reviewed in [131]). It is a leading cause of maternal morbidity and mortality, account- ing for an estimated 50,000 deaths annually (reviewed in [40]). Preeclampsia is complex, affecting multiple systems, and is diagnosed after the 20th week of pregnancy by the onset of hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) in the presence of proteinuria (300 mg or greater over 24 hours) [129]. Preeclampsia is also associated with a multitude of physio- logical changes which lead to vascular dysfunction and threaten maternal health. Aside from the vasculature, it affects the central nervous system, lungs, liver, kidneys, and the heart. Preeclampsia may increase the risk for eclampsia (seizures), and the development of HELLP syndrome. HELLP syndrome can lead to serious complications, includ- ing disseminated intravascular coagulation, acute renal failure, and pulmonary edema, which may cause maternal illness and/or death (reviewed in [133]). Preeclampsia is DOI:10.1111/micc.12079 Invited Review 4 ª 2013 John Wiley & Sons Ltd