Jaewang Ghim1, Jin-Sook Moon1, Chang Sup Lee1, Junyeop Lee1, Parkyong Song1, Areum Lee1, Jin-Hyeok Jang1, Dayea Kim1, Jong Hyuk Yoon1, Young Jun Koh1, Chaithanya Chelakkot1, Byung Jun Kang1, Jung-Min Kim1, Kyung Lock Kim1, Yong Ryoul Yang1, Youngmi Kim1, Sun-Hee Kim1, Daehee Hwang1, Pann-Ghill Suh1, Gou Young Koh1, Young-Yun Kong1, Sung Ho Ryu2. 1. 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.). 2. 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.
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. 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.
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.
Authors: Priyanka Trivedi; Ramya K Kumar; Ashwin Iyer; Sarah Boswell; Casimiro Gerarduzzi; Vivekkumar P Dadhania; Zach Herbert; Nikita Joshi; James P Luyendyk; Benjamin D Humphreys; Vishal S Vaidya Journal: J Am Soc Nephrol Date: 2017-08-16 Impact factor: 10.121
Authors: Sung Kyun Lee; Sang Doo Kim; Minsoo Kook; Ha Young Lee; Jaewang Ghim; Youngwoo Choi; Brian A Zabel; Sung Ho Ryu; Yoe-Sik Bae Journal: J Exp Med Date: 2015-08-17 Impact factor: 14.307
Authors: Jonathan Trujillo Viera; Rabih El-Merahbi; Bernhard Nieswandt; David Stegner; Grzegorz Sumara Journal: PLoS One Date: 2016-06-14 Impact factor: 3.240