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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, 2008April 14, 2008; DOI 10.1182/blood-2007-12-130567.
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Submitted December 28, 2007
Accepted March 14, 2008
Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1 
Nitin Patel, Caryn S Gonsalves, Punam Malik M.D., and Vijay K Kalra*
Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, United States
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
* Corresponding author; email: vkalra{at}usc.edu.
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) that activates monocytes to induce proinflammatory cytochemokines contributing to the baseline inflammation and severity in SCD. Herein, we observed that PlGF increased expression of endothelin-1 (ET-1) and endothelin-B receptor (ET-BR) from human pulmonary microvascular endothelial cells (HPMVEC) 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; an effect 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 HPMVEC 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 a 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, like thalassemia, and may contribute to inflammation and PHT seen in these diseases.
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