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Endothelial deletion of phospholipase d2 reduces hypoxic response and pathological angiogenesis
- Endothelial deletion of phospholipase d2 reduces hypoxic response and pathological angiogenesis
- Ghim, J.[Ghim, Jae Wang]; Moon, J.-S.[Moon, Jin Sook]; Lee, C.S.[Lee, Chang Sup]; Lee, J.[Lee, Jun Yeop]; Song, P.[Song, Park Yong]; Lee, A.[Lee, A Reum]; Jang, J.-H.[Jang, Jin Hyeok]; Kim, D.[Kim, Da Yea]; Yoon, J.H.[Yoon, Jong Hyuk]; Koh, Y.J.[Koh, Young Jun]; Chelakkot, C.[Chelakkot, Chaithanya]; Kang, B.J.[Kang, Byung Jun]; Kim, J.-M.[Kim, Jung Min]; Kim, K.L.[Kim, Kyung Lock]; Yang, Y.R.[Yang, Yong Ryoul]; Kim, Y.[Kim, Young Mi]; Kim, S.-H.[Kim, Sun Hee]; Hwang, D.[Hwang, Dae Hee]; Suh, P.-G.[Suh, Pann Ghill]; Koh, G.Y.[Koh, Gou Young]; Kong, Y.-Y.[Kong, Youn Gyun]; Ryu, S.H.[Ryu, Sung Ho]
- DGIST Authors
- Hwang, D.[Hwang, Dae Hee]
- Issue Date
- Arteriosclerosis, Thrombosis, and Vascular Biology, 34(8), 1697-1703
- Article Type
- 6 Phosphofructo 2 Kinase; Angiogenesis; Animal Experiment; Animal Model; Animals; Animals, Newborn; Anoxia; Brain Derived Neurotrophic Factor Receptor; Cancer Transplantation; Carcinogenesis; Carcinoma, Lewis Lung; Caspase 3; Cell Adhesion Molecule; Cell Function; Cell Hypoxia; Cell Migration; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Controlled Study; Disease Models, Animal; Endothelial Cell; Endothelial Cells; Endothelium Cell; Fructose 2,6 Bisphosphatase; Gene Expression; Gene Expression Regulation; Gene Targeting; Heme Oxygenase-1; Human; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Hypoxia-Inducible Factor-1; Hypoxia-Inducible Factor-1 Alpha; Hypoxia-Inducible Factor-1, Alpha Subunit; In Vivo Study; Knockout Mouse; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse; Neo-Vascularization, Pathologic; Nerve Sprouting; Nitric Oxide Synthase; Non-Human; Oxidative Stress; Oxygen-Induced Retinopathy; Phospholipase D; Phospholipase D2; Priority Journal; Reduced Nicotinamide Adenine Dinucleotide Phosphate; Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2; Regulatory Mechanism; Retinal Neovascularization; Retinal Vessels; RNA Interference; Time Factors; Tissue-Culture Techniques; Transfection; Tumor Growth; Upregulation; Vascular Tumor; Vasculotropin A
- Objective - Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis that occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α and target genes are important for the angiogenic functions of ECs. Phospholipase D2 (PLD2) is a crucial signaling mediator that stimulates the production of the second messenger phosphatidic acid. PLD2 is involved in various cellular functions; however, its specific roles in ECs under hypoxia and in vivo angiogenesis remain unclear. In the present study, we investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo. Approach And Results - Pld2 knockout ECs exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of hypoxia-inducible factor-1α target genes, including VEGF, PFKFB3, HMOX-1, and NTRK2. Consistent with this, PLD2 contributed to hypoxia-induced hypoxia-inducible factor-1α expression at the translational level. The roles of PLD2 in hypoxia-induced in vivo pathological angiogenesis were assessed using oxygen-induced retinopathy and tumor implantation models in endothelial-specific Pld2 knockout mice. Pld2 endothelial-specific knockout retinae showed decreased neovascular tuft formation, despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 endothelial-specific knockout mice. Conclusions - Our findings demonstrate a novel role for endothelial PLD2 in the survival and migration of ECs under hypoxia via the expression of hypoxia-inducible factor-1α and in pathological retinal angiogenesis and tumor angiogenesis in vivo. © 2014 American Heart Association, Inc.
- Lippincott Williams and Wilkins
- Related Researcher
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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