title: Endothelial deletion of phospholipase D2 reduces hypoxic response and pathological angiogenesis.
abstract: 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.
  
  
  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.
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Jaewang
authors.initials: J
authors.lastname: Ghim
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Moon
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Chang Sup
authors.initials: CS
authors.lastname: Lee
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Junyeop
authors.initials: J
authors.lastname: Lee
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Parkyong
authors.initials: P
authors.lastname: Song
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Areum
authors.initials: A
authors.lastname: Lee
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Jin-Hyeok
authors.initials: JH
authors.lastname: Jang
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Dayea
authors.initials: D
authors.lastname: Kim
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Jong Hyuk
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Koh
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Chaithanya
authors.initials: C
authors.lastname: Chelakkot
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Byung Jun
authors.initials: BJ
authors.lastname: Kang
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Kyung Lock
authors.initials: KL
authors.lastname: Kim
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.).
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.affiliation: From the Department of Life Sciences (J.G., J.-S.M., C.S.L., P.S., A.L., D.K., J.H.Y., B.J.K, J.-M.K., K.L.K., Y.R.Y., Y.K., S.-H.K., P.-G.S., Y.-Y.K., S.H.R.), School of Interdisciplinary Bioscience and Bioengineering (J.-H.J., D.H., S.H.R.), Division of Integrative Biosciences and Biotechnology (C.C., S.H.R.), and Department of Chemical Engineering (D.H.), Pohang University of Science and Technology, Pohang, Korea; and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.L., Y.J.K, G.Y.K.). sungho@postech.ac.kr ykong@snu.ac.kr.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018827:Carcinoma, Lewis Lung / Q000098:blood supply*; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D010739:Phospholipase D / Q000172:deficiency* / Q000235:genetics; D034622:RNA Interference; D015861:Retinal Neovascularization / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D012171:Retinal Vessels / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C105606:phospholipase D2; D010739:Phospholipase D
keywords: angiogenesis; endothelial cell; hypoxia-inducible factor-1; phospholipase D2