CYP1B1 and Retinopathy of Prematurity

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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.