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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, Jae WangMoon, Jin SookLee, Chang SupLee, Jun YeopSong, Park YongLee, A ReumJang, Jin HyeokKim, Da YeaYoon, Jong HyukKoh, Young JunChelakkot, ChaithanyaKang, Byung JunKim, Jung MinKim, Kyung LockYang, Yong RyoulKim, Young MiKim, Sun HeeHwang, Dae HeeSuh, Pann GhillKoh, Gou YoungKong, Youn GyunRyu, Sung Ho
DGIST Authors
Hwang, Dae Hee
Issued Date
Article Type
6 Phosphofructo 2 KinaseAngiogenesisAnimal ExperimentAnimal ModelAnimalsAnimals, NewbornAnoxiaBrain Derived Neurotrophic Factor ReceptorCancer TransplantationCarcinogenesisCarcinoma, Lewis LungCaspase 3Cell Adhesion MoleculeCell FunctionCell HypoxiaCell MigrationCell MovementCell ProliferationCell SurvivalCells, CulturedControlled StudyDisease Models, AnimalEndothelial CellEndothelial CellsEndothelium CellFructose 2,6 BisphosphataseGene ExpressionGene Expression RegulationGene TargetingHeme Oxygenase-1HumanHuman Umbilical Vein Endothelial CellsHumansHypoxiaHypoxia-Inducible Factor-1Hypoxia-Inducible Factor-1 AlphaHypoxia-Inducible Factor-1, Alpha SubunitIn Vivo StudyKnockout MouseMiceMice, Inbred C57BLMice, KnockoutMouseNeo-Vascularization, PathologicNerve SproutingNitric Oxide SynthaseNon-HumanOxidative StressOxygen-Induced RetinopathyPhospholipase DPhospholipase D2Priority JournalReduced Nicotinamide Adenine Dinucleotide PhosphateReduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2Regulatory MechanismRetinal NeovascularizationRetinal VesselsRNA InterferenceTime FactorsTissue-Culture TechniquesTransfectionTumor GrowthUpregulationVascular TumorVasculotropin 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
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Department of New Biology Systems Biology and Medicine Lab 1. Journal Articles


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