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题名: Functional characterization of KlippelTrenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis
作者: Chen, Di1, 2; Li, Lei1; Tu, Xin1, 2; Yin, Zhan1, 3; Wang, Qing1, 2, 4
通讯作者: Yin, Z (reprint author), Ctr Human Genome Res, 1037 Luoyu Rd, Wuhan, Peoples R China.
关键词: KLIPPEL-TRENAUNAY-SYNDROME ; CORONARY-ARTERY-DISEASE ; LYMPHATIC ENDOTHELIAL-CELLS ; PHOSPHATIDYLINOSITOL 3-KINASE ; MOLECULAR CHARACTERIZATION ; KINASE PATHWAYS ; TRANSGENIC MICE ; SMOOTH-MUSCLE ; ZEBRAFISH ; EXPRESSION
刊名: HUMAN MOLECULAR GENETICS
发表日期: 2013-03-01
DOI: 10.1093/hmg/dds501
卷: 22, 期:5, 页:963-976
收录类别: SCI
文章类型: Article
部门归属: [Chen, Di; Li, Lei; Tu, Xin; Yin, Zhan; Wang, Qing] Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan, Peoples R China; [Chen, Di; Tu, Xin; Wang, Qing] Huazhong Univ Sci & Technol, Ctr Human Genome Res, Cardio X Inst, Wuhan 430074, Peoples R China; [Yin, Zhan] Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China; [Wang, Qing] Cleveland Clin, Dept Mol Cardiol, Lerner Res Inst, Ctr Cardiovasc Genet, Cleveland, OH 44106 USA
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
资助者: Fundamental Research Funds for the Central Universities [2010MS015]; China National Basic Research Program (973 Program) [2013CB531101]; State Key Laboratory of Freshwater Ecology and Biotechnology [2011FB16]; Hubei Province Natural Science Key Program [2008CDA047]; Key Academic Program Leader Award of Wuhan City [200951830560]
类目[WOS]: Biochemistry & Molecular Biology ; Genetics & Heredity
研究领域[WOS]: Biochemistry & Molecular Biology ; Genetics & Heredity
摘要: Specification of arteries and veins is a key process for establishing functional vasculature during embryogenesis and involves distinctly different signaling mechanisms. Vascular endothelial growth factor-A (VEGFA) is required for differentiation of arteries; however, the upstream angiogenic factor for vein specification is unknown. KlippelTrenaunay syndrome (KTS) is a congenital vascular disease associated with capillary and venous malformations (VMs), but not with arterial defects. We have previously reported that upregulation of angiogenic factor AGGF1 is associated with KTS, but the molecular mechanism is not clear. Here, we show that AGGF1 is involved in establishing venous identity in zebrafish embryos. Overexpression of AGGF1 led to increased angiogenesis and increased lumen diameter of veins, whereas knockdown of AGGF1 expression resulted in defective vasculogenesis and angiogenesis. Overexpression of AGGF1 increased expression of venous markers (e.g. flt4), but had little effect on arterial markers (e.g. notch5). Knockdown of AGGF1 expression resulted in a loss of venous identity (loss of expression of flt4, ephb4 and dab2), but had no effect on the expression of arterial development. We further show that AGGF1 activates AKT, and that decreased AGGF1 expression inhibits AKT activation. Overexpression of constitutively active AKT rescues the loss of venous identity caused by AGGF1 downregulation. Our study establishes AGGF1 as an angiogenic factor with an important role in the specification of vein identity and suggests that AGGF1-mediated AKT signaling is responsible for establishing venous cell fate. We propose that increased AGGF1 expression leads to increased vein differentiation by inducing activation of AKT signaling, resulting in VMs s in KTS patients.
英文摘要: Specification of arteries and veins is a key process for establishing functional vasculature during embryogenesis and involves distinctly different signaling mechanisms. Vascular endothelial growth factor-A (VEGFA) is required for differentiation of arteries; however, the upstream angiogenic factor for vein specification is unknown. KlippelTrenaunay syndrome (KTS) is a congenital vascular disease associated with capillary and venous malformations (VMs), but not with arterial defects. We have previously reported that upregulation of angiogenic factor AGGF1 is associated with KTS, but the molecular mechanism is not clear. Here, we show that AGGF1 is involved in establishing venous identity in zebrafish embryos. Overexpression of AGGF1 led to increased angiogenesis and increased lumen diameter of veins, whereas knockdown of AGGF1 expression resulted in defective vasculogenesis and angiogenesis. Overexpression of AGGF1 increased expression of venous markers (e.g. flt4), but had little effect on arterial markers (e.g. notch5). Knockdown of AGGF1 expression resulted in a loss of venous identity (loss of expression of flt4, ephb4 and dab2), but had no effect on the expression of arterial development. We further show that AGGF1 activates AKT, and that decreased AGGF1 expression inhibits AKT activation. Overexpression of constitutively active AKT rescues the loss of venous identity caused by AGGF1 downregulation. Our study establishes AGGF1 as an angiogenic factor with an important role in the specification of vein identity and suggests that AGGF1-mediated AKT signaling is responsible for establishing venous cell fate. We propose that increased AGGF1 expression leads to increased vein differentiation by inducing activation of AKT signaling, resulting in VMs s in KTS patients.
关键词[WOS]: KLIPPEL-TRENAUNAY-SYNDROME ; CORONARY-ARTERY-DISEASE ; LYMPHATIC ENDOTHELIAL-CELLS ; PHOSPHATIDYLINOSITOL 3-KINASE ; MOLECULAR CHARACTERIZATION ; KINASE PATHWAYS ; TRANSGENIC MICE ; SMOOTH-MUSCLE ; ZEBRAFISH ; EXPRESSION
语种: 英语
WOS记录号: WOS:000314897600011
ISSN号: 0964-6906
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/19342
Appears in Collections:水生生物分子与细胞生物学研究中心_期刊论文

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作者单位: 1.Coll Life Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan, Peoples R China
2.Huazhong Univ Sci & Technol, Ctr Human Genome Res, Cardio X Inst, Wuhan 430074, Peoples R China
3.Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China
4.Cleveland Clin, Dept Mol Cardiol, Lerner Res Inst, Ctr Cardiovasc Genet, Cleveland, OH 44106 USA
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