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Blood, 1 August 2008, Vol. 112, No. 3, pp. 856-865. Prepublished online as a Blood First Edition Paper on April 14, 2008; DOI 10.1182/blood-2007-12-130567. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-12-130567v1 blood-2007-12-130567v2 112/3/856    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Patel, N. Articles by Kalra, V. K. Search for Related Content PubMed PubMed Citation Articles by Patel, N. Articles by Kalra, V. K. Related Collections Hemostasis, Thrombosis, and Vascular Biology Red Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1 Nitin Patel1, Caryn S. Gonsalves1, Punam Malik2,*, and Vijay K. Kalra1,* 1 Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles; and 2 Division of Hematology, Cincinnati Children's Hospital Medical Center, OH Pulmonary hypertension (PHT) develops in sickle cell disease (SCD) and is associated with high mortality. We previously showed that erythroid cells produce placenta growth factor (PlGF), which activates monocytes to induce proinflammatory cytochemokines, contributing to the baseline inflammation and severity in SCD. In this study, we observed that PlGF increased expression of endothelin-1 (ET-1) and endothelin-B receptor (ET-BR) from human pulmonary microvascular endothelial cells (HPMVECs) and monocytes, respectively. PlGF-mediated ET-1 and ET-BR expression occurred via activation of PI-3 kinase, reactive oxygen species and hypoxia inducible factor-1 (HIF-1). PlGF increased binding of HIF-1 to the ET-1 and ET-BR promoters; this effect was abrogated with mutation of hypoxia response elements in the promoter regions and HIF-1 siRNA and confirmed by chromatin immunoprecipitation analysis. Furthermore, PlGF-mediated ET-1 release from HPMVECs and ET-BR expression in monocytes creates a PlGF–ET-1–ET-BR loop, leading to increased expression of MCP-1 and IL-8. Our studies show that PlGF-induced expression of the potent vasoconstrictor ET-1 and its cognate ET-BR receptor occur via activation of HIF-1, independent of hypoxia. PlGF levels are intrinsically elevated from the increased red cell turnover in SCD and in other chronic anemia (eg, thalassemia) and may contribute to inflammation and PHT seen in these diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: It really IS the red cell Marilyn J. Telen Blood 2008 112: 459-460. [Full Text] [PDF] This article has been cited by other articles: E. Belaidi, M. Joyeux-Faure, C. Ribuot, S. H. Launois, P. Levy, and D. Godin-Ribuot Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. J. Am. Coll. Cardiol., April 14, 2009; 53(15): 1309 - 1317. [Abstract] [Full Text] [PDF] N. Patel, C. S. Gonsalves, M. Yang, P. Malik, and V. K. Kalra Placenta growth factor induces 5-lipoxygenase-activating protein to increase leukotriene formation in sickle cell disease Blood, January 29, 2009; 113(5): 1129 - 1138. [Abstract] [Full Text] [PDF]

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