CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression

• Published in: Blood Vol. 113; no. 3; pp. 744 - 754
• Main Authors: Tang, Yixin, Scheef, Elizabeth A., Wang, Shoujian, Sorenson, Christine M., Marcus, Craig B., Jefcoate, Colin R., Sheibani, Nader
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2009; American Society of Hematology
• Series: Vascular Biology
• Subjects: Animals; Antioxidants - pharmacology; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Blotting, Western; Cell Movement; Cytochrome P-450 CYP1B1; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Gene Expression; Gene Expression Regulation; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Lipid Peroxidation - drug effects; Mice; Mice, Mutant Strains; Microscopy, Fluorescence; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; Phenotype; Reactive Oxygen Species - metabolism; Retinal Vessels - drug effects; Retinal Vessels - metabolism; Retinal Vessels - pathology; RNA, Small Interfering; Thrombospondins - biosynthesis; Vascular Biology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-03-145219

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 (ECs) 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−/− ECs 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 and were reversed by administration of an antioxidant. Reexpression of CYP1B1 in CYP1B1−/− ECs resulted in down-regulation of TSP2 expression and restoration of capillary morphogenesis. A TSP2 knockdown in CYP1B1−/− ECs also restored capillary morphogenesis. Thus, CYP1B1 metabolizes cell products that modulate intracellular oxidative stress, which enhances production of TSP2, an inhibitor of EC migration and capillary morphogenesis. Evidence is presented that similar changes occur in retinal endothelium in vivo to limit neovascularization.