Hindawi Publishing Corporation Journal of Pregnancy Volume 2012, Article ID 374047, 6 pages doi:10.1155/2012/374047 Review Article Preeclampsia, Hypoxia, Thrombosis, and Inﬂammation Amir A. Shamshirsaz, Michael Paidas, and Graciela Krikun Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Yale University, New Haven, CT 06520, USA Correspondence should be addressed to Graciela Krikun, graciela.krikun@yale.edu Received 24 August 2011; Accepted 4 November 2011 Academic Editor: Nikolaos Vrachnis Copyright © 2012 Amir A. Shamshirsaz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Reductions in uteroplacental ﬂow initiate a cascade of molecular eﬀects leading to hypoxia, thrombosis, inﬂammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes. In this review, we detail these eﬀects and their relationship to preeclampsia (PE) and intrauterine growth restriction (IUGR). 1. Introduction PE is universally deﬁned as hypertension and signiﬁcant pro- teinuria developed at or after 20 weeks of pregnancy in an otherwise normotensive woman [1–3]. PE is a multisystem disorder which complicates 3–14% of all pregnancies and about 5–8% of pregnancies in the United States [1]. The disease is mild in 75% of cases in the United States, and severe in 25% of cases [4]. Ten percent of PE occurs in pregnancies less than 34 weeks of gestation. The incidence of PE has risen in the USA in the last decades [5]. This ﬁnding might be related to an increased prevalence of predisposing disorders, such as maternal age, chronic hypertension, diabetes, prepregnancy obesity, and multiple births [5–7]. Overall, 10%–15% of direct maternal deaths are associated with PE in low- and middle-income countries and the proportion is similar in high-income countries [8, 9]. Furthermore, severe PE is a major cause of maternal morbidity (i.e., stroke and liver rupture) and negative long- term outcomes (i.e., cardiovascular disease and diabetes mel litus) as well as adverse perinatal eﬀects, such as prematurity and intrauterine growth restriction [5, 10]. While much research has been devoted toward this topic, the cause of PE still remains elusive. Two diﬀerent theories have emerged: (1) vascular-ischemic origin of PE and (2) impaired immune response [11]. A current hypothesis uni- ﬁes these concepts where an altered immune response leads to disturbed placental function early in pregnancy with consequent syncytiotrophoblast ischemia and shedding of products that extensively damage endothelial integrity. This in turn results in an exponential production of multiple factors such as cytokines and growth factors leading to the clinical manifestations of PE [11]. How the immune response can activate the cascade process is still unknown but it is pro- posed to act in synergy with additional exacerbating factors such as predisposing maternal and ambient factors [12]. 2. Angiogenic Factors and PE Angiogenic factors and their receptors are important reg- ulators of placental vascular development [13]. The most widely studied serum markers for PE, to date, are vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Antagonists include soluble fms-like tyrosine kinase 1 (sFlt-1, also known as sVEGFR1), and soluble endoglin (sEng) [13]. sFlt-1 is a truncated splice variant of the membrane- bound Flt1; it consists of the extracellular binding domain without the intracellular signaling domain. Several studies demonstrated the association of increased sFlt-1 with PE [14, 15]. Evidence for the involvement of sFlt1 in the occurrence of PE was initially provided by an animal model in which gravid rats were infected with a recombinant adenovirus encoding sFlt1 and compared to animals infected with the empty con- trol adenovirus. The animals infected with sFlt1 developed