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C. Meagher, M. Nakanishi, N. LeClair, W. C. Greene, E. C. Strauss; Ikk2 Mediates Coordinate Regulation of Inflammatory Angiogenesis and Lymphangiogenesis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3741.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate our hypothesis that IΚB-kinase-2 (IKK2) initiates and controls the coordinate regulation of inflammatory angiogenesis and lymphangiogenesis in the cornea.
Inflammatory angiogenesis and lymphangiogenesis was induced in a cautery model and characterized using confocal microscopy, immunoblotting, in vivo small molecule inhibition of IKK2 and JNK, and quantitative PCR.
Angiogenesis and lymphangiogenesis show an intimate spatio-temporal association with inflammatory diseases. However, the fundamental signaling mechanisms initiating and coordinating angiogenesis, lymphangiogenesis and inflammation remain obscure. IΚB-kinase2 (IKK2) is a master regulator of inflammation through activation of the transcription factor NF-ΚB. Moreover, aberrant expression of NF-ΚB has been implicated in many cancers. In this study, we utilized a cautery model to investigate the role of IKK2 in initiating and controlling inflammatory angiogenesis and lymphangiogenesis in the cornea. Our results show that selective inhibition of IKK2 with a small molecule antagonist prevented the onset of VEGF-A induced inflammatory angiogenesis and VEGF-C/VEGF-D stimulated lymphangiogenesis. Moreover, active inflammatory angiogenic and lymphangiogenic responses were rapidly arrested following selective inhibition of IKK2. These findings were also confirmed in mice deficient for the p50 subunit of NF-ΚB.
Our results indicate that IKK2 initiates and controls VEGF-A induced angiogenesis and VEGF-D stimulated lymphangiogenesis through c-fos mediated AP-1 activity. Furthermore, our data suggests that VEGF-C is controlled directly by IKK2/NF-ΚB. Overall, our findings suggest that IKK2 is an essential upstream regulatory link coordinating inflammatory angiogenesis and lymphangiogenesis and may represent a pivotal therapeutic target for preventing or terminating pathologic angiogenesis and lymphangiogenesis.
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