Regulation of Placental Angiogenesis DONG-BAO CHEN,* AND JING ZHENG † *Department of Obstetrics & Gynecology, University of California, Irvine, California, USA; † Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, USA Address for correspondence: Dong-bao Chen, Ph.D., Department of Obstetrics & Gynecology, University of California, Irvine, CA 92697, USA. E-mail: dongbaoc@uci.edu Received 22 April 2013; accepted 21 August 2013. ABSTRACT Ample interest has been evoked in using placental angiogenesis as a target for the development of diagnosis tools and potential therapeutics for pregnancy complications based on the knowledge of placental angiogenesis in normal and aberrant pregnancies. Although these goals are still far from reach, one would expect that two complementary processes should be balanced for therapeutic angiogenesis to be successful in restoring a mature and functional vascular network in the placenta in any pregnancy complication: (i) pro-angiogenic stimulation of new vessel growth and (ii) anti- angiogenic inhibition of vessel overgrowth. As the best model of physiological angiogenesis, investigations of placental angiogenesis provide critical insights not only for better understanding of normal placental endothelial biology but also for the development of diagnosis tools for pregnancy complications. Such investigations will potentially identify novel pro-angiogenic factors for therapeutic intervention for tissue damage in various obstetric complications or heart failure or anti-angiogenic factors to target on cancer or vision loss in which circulation needs to be constrained. This review summarizes the genetic and molecular aspects of normal placental angiogenesis as well as the signaling mechanisms by which the dominant angiogenic factor vascular endothelial growth factor regulates placental angiogenesis with a focus on placental endothe- lial cells. Key words: angiogenesis, placenta, VEGF, transcription, signaling Abbreviations used: Akt1, V-akt murine thymoma viral oncogene homolog 1; Arnt, arylhydrocarbon receptor nuclear translocator; BAD, Bcl-2-associated death promoter; Bcl2, B-cell CLL/lymphoma; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal- regulated kinase; FGF2, fibroblast growth factor 2; Flt1, fms-related tyrosine kinase 1; HIF, hypoxia-inducible factor; iNOS, inducible NOS; JNK, Jun N-terminal kinase; KDR, kinase insert domain receptor; MAPK, mitogen-activated protein kinase; nNOS, neuronal NOS; NO, nitric oxide; PI3K, phosphotidylinositol-3-kinase; PlGF, placenta growth factor; PPARc, peroxisome proliferator-activated receptor-c; Ptdlns(4,5)P2, phosphatidylinositol 4,5-bisphosphate; RPR, proliferin-related protein; RXR, retinoid X receptor; TGF-b1, transforming growth factor-b1; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptors. Please cite this paper as: Chen D-b, Zheng J. Regulation of placental angiogenesis. Microcirculation 00: 000–000, 2013. INTRODUCTION Sprouting new blood vessels from existing ones is called angiogenesis [39]. In a healthy adult body, angiogenesis occurs for healing wounds to restore blood flow to tissues after injury or insult and in various pathological conditions such as cancer and retinopathy [16]. In female eutherians, it occurs normally during the menstrual or estrous cycle to transform the ovulated follicles into the corpus luteum for progesterone synthesis and to rebuild the uterine endo- metrium receptive for the implanting embryos [100]. It requires endothelial proliferation, migration, and differentia- tion within the preexisting blood vessels as they send out capillary sprouts to initiate the formation of new tube-like structures, and secondary vasodilatation to enhance circulation and nutrient uptake [39]. This multistep process begins with a rise in local and/or systemic angiogenic factors, followed by breakdown of endothelial basement membrane to facilitate endothelial migration and proliferation. Endothelial differentiation leads to newly formed tube-like structures that stabilizes as mature vessels with the recruitment of peri- cytes or smooth muscle cells [15,50]. Deranged angiogenesis has a major impact on human health and contributes to the pathogenesis of numerous vascular diseases that are caused by either excessive angiogenesis in tumors, retinopathy, and cavernous hemangioma or insufficient angiogenesis in atherosclerosis, hypertension, diabetes, and restenosis [16]. In eutherians, shortly after the embryo is implanted, its trophectoderm develops into the placenta. This ephemeral organ is unique to the pregnancy of these creatures, critically enough to evolutionally escape them from distinction. It DOI:10.1111/micc.12093 Invited Review ª 2013 John Wiley & Sons Ltd 1