title: Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1 alpha.
abstract: 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 alpha (HIF-1 alpha). PlGF increased binding of HIF-1 alpha 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 alpha 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 alpha, 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Patel
authors.forename: Caryn S
authors.initials: CS
authors.lastname: Gonsalves
authors.forename: Punam
authors.initials: P
authors.lastname: Malik
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kalra
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis; D009000:Monocytes / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000502:physiology*; D011652:Pulmonary Circulation; D044023:Receptor, Endothelin B / Q000235:genetics*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D044023:Receptor, Endothelin B; D000072483:Placenta Growth Factor