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Blood, 15 January 2009, Vol. 113, No. 3, pp. 744-754.
Prepublished online as a Blood First Edition Paper on November 12, 2008; DOI 10.1182/blood-2008-03-145219.
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Submitted March 14, 2008
Accepted October 2, 2008
CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression
Yixin Tang, Elizabeth A Scheef, Shoujian Wang, Christine M Sorenson, Craig B Marcus, Colin R Jefcoate, and Nader Sheibani*
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine, Madison, WI, United States
Department of Pediatrics, University of Wisconsin School of Medicine, Madison, WI, United States
Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
Department of Pharmacology, University of Wisconsin School of Medicine, Madison, WI, United States
* Corresponding author; email: nsheibanikar{at}wisc.edu.
Reactive species derived from cell oxygenation processes play an important role in vascular homeostasis and the pathogenesis of many diseases including retinopathy of prematurity. We show that CYP1B1-deficient (CYP1B1-/-) mice fail to elicit a neovascular response during oxygen-induced ischemic retinopathy. In addition, the retinal endothelial cells (EC) prepared from CYP1B1-/- mice are less adherent, less migratory, and fail to undergo capillary morphogenesis. These aberrant cellular responses were completely reversed when oxygen levels were lowered or an antioxidant added. CYP1B1-/- EC exhibited increased oxidative stress, and expressed increased amounts of the antiangiogenic factor thrombospondin-2 (TSP2). Increased lipid peroxidation and TSP2 were both observed in retinas from CYP1B1-/- mice, which were reversed by administration of an antioxidant. Re-expression of CYP1B1 in CYP1B1-/- EC resulted in down-regulation of TSP2 expression and restoration of capillary morphogenesis. A TSP2 knockdown in CYP1B1-/- EC also restored capillary morphogenesis. Thus, CYP1B1 metabolizes cell products that modulate intracellular oxidative stress, which enhances TSP2 production, an inhibitor of EC migration and capillary morphogenesis. Evidence is presented that similar changes occur in retinal endothelium in vivo to limit neovascularization.
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