CYP1B1 and Retinopathy of Prematurity

CYP1B1 和早产儿视网膜病变

• 批准号: 7649188
• 负责人: NADER SHEIBANI
• 金额: $ 35.06万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649188
• 关键词: Acetylcysteine; Address; Affect; Air; Angiogenesis Inhibition; Angiogenesis Inhibitors; Antioxidants; Aryl Hydrocarbon Receptor; Blood Vessels; Blood capillaries; CYP1B1 gene; Capillary Endothelial Cell; Cardiovascular system; Cells; Characteristics; Cytochromes; Data; Development; Diabetic Retinopathy; Disease; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Excision; Exhibits; Eye; Eye diseases; Family; Gene Targeting; Genes; Glaucoma; Homeostasis; Human; In Vitro; Irido-corneo-trabecular dysgenesis; Isoprostanes; Link; Macular degeneration; Mediating; Messenger RNA; Metabolism; Mitochondria; Molecular; Morphogenesis; Mus; Mutation; NADPH Oxidase; Neural Crest; Open-Angle Glaucoma; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Phenotype; Physiological; Play; Polyunsaturated Fatty Acids; Premature Infant; Process; Proteins; Reactive Oxygen Species; Regulation; Regulatory Pathway; Research; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Smooth Muscle Myocytes; Source; Structure of sinus venosus of sclera; Testing; Trabecular meshwork structure; Vascular Endothelial Cell; Vascularization; Xanthine Oxidase; angiogenesis; anterior chamber; atheroprotective; attenuation; capillary; cell type; density; effective therapy; hindbrain; in vivo; insight; matrigel; member; neovascularization; new growth; novel; retinal angiogenesis; shear stress; thrombospondin 2; transcription factor

The expression of specific cytochrome P450s (CYPs) in vascular smooth muscle cells and endothelial cells (EC). and the critical contribution of their products to vascular function suggest important roles for these genes in vascular homeostasis. Although lack of CYP1 B1 is shown to influence the function and development of the trabecular meshwork. Its physiological role in the development of retinal vasculature and angiogenesis has not been previously studied. Our preliminary data indicate that CYP1 B1 plays an essential role in retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy (aiR). The CYP1 B1-deficient (CYP1 B1-/-) mice exhibit reduced retinal vascular density and fail to neovascularize their retina during aiR. Furthermore. retinal EC prepared from CYP1B1-/- mice are less migratory and fail to undergo capillary morphogenesis in Matrigel. These cells also express increased amounts of thrombospondin-2 (TSP2). an endogenous inhibitor of angiogenesis whose expression is modulated by cellular oxidative stress. Our hypothesis is that CYP1 B1 plays a central role in maintaining the redox state of the endothelium in check, such that in its absence increased oxidative stress promotes sustained activation of NF-KB and TSP2 expression, and inhibits angiogenesis. We have now shown that changes in TSP2 expression mediate the effects of CYP1 B1-deficiency on retinal vascularization in vivo and capillary morphogenesis of retinal EC in culture. We have also shown increased oxidative state mediates these effects of CYP1B1-deficiency on retinal neovascularization during OIR and can be reversed in the presence of an antioxidant. In addition changes in CYP1 B 1 expression are sufficient to affect TSP2 expression and retinal EC capillary morphogenesis in vitro. Therefore these changes are modulated by the intracellular oxidative stress in a CYP1 B1 dependent manner. Here we will determine the source of reactive oxygen species and will delineate the potential regulatory role of redox sensitive transcription factors NF-KB in increased TSP2 expression. We will also determine whether expression of NF-KB is modulated by CYP1 B1 through removal of oxygenation products. Understanding how CYP1 B1 and its metabolites regulate retinal vascular homeostasis will provide insight into CYP1 B1 mechanisms of action and aid in the development of alternative ways to modulate retinal angiogenesis.

血管平滑肌细胞和内皮细胞 (EC) 中特异性细胞色素 P450 (CYP) 的表达。他们的产品对血管功能的关键贡献表明这些基因在血管稳态中发挥着重要作用。尽管 CYP1 B1 的缺乏被证明会影响小梁网的功能和发育。此前尚未研究过其在视网膜脉管系统发育和血管生成中的生理作用。我们的初步数据表明，CYP1 B1 在氧诱导缺血期间视网膜血管发育和新生血管形成中发挥重要作用 视网膜病变（aiR）。 CYP1 B1 缺陷（CYP1 B1-/-）小鼠表现出视网膜血管密度降低，并且在 aiR 过程中无法使视网膜新生血管化。此外。从 CYP1B1-/- 小鼠制备的视网膜 EC 迁移性较差，并且无法在基质胶中进行毛细血管形态发生。这些细胞还表达增加量的血小板反应蛋白-2 (TSP2)。一种内源性血管生成抑制剂，其表达受细胞氧化应激调节。我们的假设是，CYP1 B1 在维持内皮氧化还原状态受控方面发挥着核心作用，因此在其缺失的情况下，氧化应激的增加会促进 NF-KB 和 TSP2 表达的持续激活，并抑制血管生成。我们现在已经证明 TSP2 表达的变化介导了 CYP1 B1 缺陷对体内视网膜血管化和培养中视网膜 EC 毛细血管形态发生的影响。我们还发现，氧化状态的增加介导了 OIR 期间 CYP1B1 缺乏对视网膜新生血管形成的影响，并且在抗氧化剂存在的情况下可以逆转。此外，CYP1 B 1 表达的变化足以影响体外TSP2表达和视网膜EC毛细血管形态发生。因此，这些变化是由细胞内氧化应激以 CYP1 B1 依赖性方式调节的。在这里，我们将确定活性氧的来源，并描述氧化还原敏感转录因子 NF-KB 在 TSP2 增加中的潜在调节作用 表达。我们还将确定 NF-KB 的表达是否受到 CYP1 B1 通过去除氧合产物的调节。了解 CYP1 B1 及其代谢物如何调节视网膜血管稳态将有助于深入了解 CYP1 B1 的作用机制，并有助于开发调节视网膜血管生成的替代方法。