| First Author | Kumar R | Year | 2022 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 42 |
| Issue | 4 | Pages | 407-427 |
| PubMed ID | 35236105 | Mgi Jnum | J:345504 |
| Mgi Id | MGI:7579545 | Doi | 10.1161/ATVBAHA.121.317182 |
| Citation | Kumar R, et al. (2022) Novel Role of Prereplication Complex Component Cell Division Cycle 6 in Retinal Neovascularization. Arterioscler Thromb Vasc Biol 42(4):407-427 |
| abstractText | BACKGROUND: The major aim of this study is to investigate whether CDC6 (cell division cycle 6), a replication origin recognition complex component, plays a role in retinal neovascularization, and if so, to explore the underlying mechanisms. METHODS: In this study, we used a variety of approaches including cellular and moleculer biological methodologies as well as global and tissue-specific knockout mice in combination with an oxygen-induced retinopathy model to study the role of CDC6 in retinal neovascularization. RESULTS: VEGFA (vascular endothelial growth factor A)-induced CDC6 expression in a time-dependent manner in human retinal microvascular endothelial cells. In addition, VEGFA-induced CDC6 expression was dependent on PLCbeta3 (phospholipase Cbeta3)-mediated NFATc1 (nuclear factor of activated T cells c1) activation. Furthermore, while siRNA-mediated depletion of PLCbeta3, NFATc1, or CDC6 levels blunted VEGFA-induced human retinal microvascular endothelial cell angiogenic events such as proliferation, migration, sprouting, and tube formation, CDC6 overexpression rescued these effects in NFATc1-deficient mouse retinal microvascular endothelial cells. In accordance with these observations, global knockdown of PLCbeta3 or endothelial cell-specific deletion of NFATc1 or siRNA-mediated depletion of CDC6 levels substantially inhibited oxygen-induced retinopathy-induced retinal sprouting and neovascularization. In addition, retroviral-mediated overexpression of CDC6 rescued oxygen-induced retinopathy-induced retinal neovascularization from inhibition in PLCbeta3 knockout mice and in endothelial cell-specific NFATc1-deficient mice. CONCLUSIONS: The above observations clearly reveal that PLCbeta3-mediated NFATc1 activation-dependent CDC6 expression plays a crucial role in VEGFA/oxygen-induced retinopathy-induced retinal neovascularization. |
