title: Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin.
abstract: Abnormal tissue factor (TF) expression has been demonstrated on blood monocytes and circulating endothelial cells in humans with sickle cell anemia. We have now studied sickle transgenic mice to help define the biology of endothelial TF expression in sickle disease. Using immunostaining of tissue sections, we find that this is confined almost exclusively to the pulmonary veins. About 15% and 13% of these exhibit TF-positive endothelium in the wild-type normal mouse and the normal human hemoglobin (HbA)-expressing control transgenic mouse, respectively. The mild sickle mouse is indistinguishable from normal (approximately 14% positive), but TF expression is significantly elevated in the moderate and severe mouse models of sickle disease (approximately 29% and approximately 41% positive, respectively). Exposure of the mild sickle mouse to hypoxia for 3 hours, followed by reoxygenation, converted its TF expression phenotype to that of the severe sickle mouse (approximately 36% positive). Pretreatment with lovastatin eliminated excessive expression of TF in the posthypoxic mild sickle mouse (approximately 16% positive) and in the more severe mouse at ambient air (approximately 21% positive). In addition to identifying tissue expression of endothelial TF in the sickle lung, these studies implicate reperfusion injury physiology in its expression and suggest a rationale for use of statins in sickle disease.
authors.affiliation: Vascular Biology Center and Divisions of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Solovey
authors.forename: Rahn
authors.initials: R
authors.lastname: Kollander
authors.forename: Arun
authors.initials: A
authors.lastname: Shet
authors.forename: Liming C
authors.initials: LC
authors.lastname: Milbauer
authors.forename: Stephana
authors.initials: S
authors.lastname: Choong
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D008148:Lovastatin / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013925:Thromboplastin / Q000032:analysis / Q000235:genetics*
chemical_list: D013925:Thromboplastin; D008148:Lovastatin