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Study on the roles of endothelial PLD2 in hypoxic response and pathological angiogenesis 원문보기

  • 저자

    김재왕

  • 학위수여기관

    포항공과대학교 일반대학원

  • 학위구분

    국내박사

  • 학과

    생명과학과

  • 지도교수

    류성호

  • 발행년도

    2014

  • 총페이지

    99

  • 키워드

    Phospholipase D Hypoxia-inducible factor-1 angiogenesis;

  • 언어

    eng

  • 원문 URL

    http://www.riss.kr/link?id=T13533478&outLink=K  

  • 초록

    Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α (HIF-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, I investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo. Here, I report that Pld2 knockout (KO) endothelial cells exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. 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 KO mice (eKO). Pld2 eKO retinae showed decreased neovascular tuft formation despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 eKO. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of HIF-1α target genes including VEGF, PFKFB3, HMOX-1, and NTRK2. Consistent with this, PLD2 contributed to hypoxia-induced HIF-1α expression at the translational level. Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α (HIF-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, I investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo. Here, I report that Pld2 knockout (KO) endothelial cells exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. 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 KO mice (eKO). Pld2 eKO retinae showed decreased neovascular tuft formation despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in Pld2 eKO. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of HIF-1α target genes including VEGF, PFKFB3, HMOX-1, and NTRK2. Consistent with this, PLD2 contributed to hypoxia-induced HIF-1α expression at the translational level.


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