Angiogenic Imbalance in the Pathophysiology of Preeclampsia: Newer Insights Yuval Bdolah, Vikas P. Sukhatme, and S. Ananth Karumanchi Angiogenesis is the process of neovascularization from preexisting blood vessels, whereas vasculogenesis is the process of blood vessel generation from angioblast precursor cells. The human placenta undergoes high levels of angiogenesis and vasculogenesis during fetal development. Additionally, the placenta undergoes a process of vascular mimicry (also referred to as pseudovasculogenesis) in which the placental cytotrophoblasts convert from an epithelial to an endothelial phenotype during normal fetal development. Failure of placental angiogenesis and pseudovasculogenesis during placental development has been linked to the pathogenesis of preeclampsia. It currently is believed that soluble factors released by the diseased placenta lead to clinical findings of preeclampsia. This article discusses placental vascular development in health and in disease, with a focus on accumulating recent evidence that the maternal clinical syndrome of preeclampsia is an antiangiogenic state resulting from an excess of anti-endothelial factors liberated by the diseased placenta. Semin Nephrol 24:548 –556 © 2004 Elsevier Inc. All rights reserved. KEYWORDS proteinuria, angiogenesis, hypertension, sVEGFR1, glomerular endotheliosis, pre- eclampsia A ngiogenesis is the formation of new capillaries from pre- existing ones, whereas vasculogenesis refers to in situ differentiation of endothelial precursors (angioblasts) into endothelial cells. Both angiogenesis and vasculogenesis are widely prevalent during normal placental development. 1 Moreover, invasive trophoblasts of the placenta undergo a unique program of conversion from an epithelial to an endo- thelial phenotype, a process referred to as pseudovasculogen- esis. 2 Ligand-receptor systems influencing angiogenesis and vasculogenesis include vascular endothelial growth factor (VEGF)/VEGF receptors, angiopoietins/tie receptors, basic fi- broblast growth factor/fibroblast growth factor receptor, and ephrin family members. Several members of these angiogenic proteins are expressed abundantly in the placenta and are thought to play an important role in normal placental vascu- lar development. When placental vascular development is deranged, serious complications such as intrauterine growth retardation and preeclampsia can occur. Preeclampsia is a multi-organ disorder that complicates approximately 5% to 7% of all pregnancies. It is associated with significant morbidity and mortality for the mother and the baby, but resolves completely postpartum. 3,4 Women with preeclampsia have a 3- to 25-fold increased risk for severe obstetric complications. 5 The clinical man- ifestations of preeclampsia consist mainly of hypertension, proteinuria, and in some cases progresses to seizures and/or the development of the HELLP syndrome (hemo- lysis, elevated liver enzymes, and low platelets). Although the underlying cause of this syndrome is much debated, the placenta is thought to play a central role in the patho- genesis of preeclampsia. It has been hypothesized that in preeclampsia, placental ischemia is an early event, leading to placental production of soluble factors that cause ma- ternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. 6,7 In this article, we describe placental vascular development in health and in disease (preeclampsia), and discuss in detail the role of soluble antiangiogenic proteins released by pre- Department of Obstetrics and Gynecology and Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. Supported by a fellowship from the American Physicians Fellowship for Medicine in Israel (Y.B.), by National Institute of Health grants (DK002825, DK64255 to S.A.K.), and the Carl W. Gottschalk award by the American Society of Nephrology. V.P.S. and S.A.K. are listed as co-inventors on a patent filed by Beth Israel Deaconess Medical Center for the use of angiogenesis-related proteins in the diagnosis and treat- ment of preeclampsia. Address reprint requests to S. Ananth Karumanchi, MD, Beth Israel Deacon- ess Medical Center, Renal Division, Dana 517, 330 Brookline Ave, Bos- ton, MA 02215. E-mail: sananth@bidmc.harvard.edu 548 0270-9295/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2004.07.003