IHB OpenIR  > 水生生物分子与细胞生物学研究中心  > 期刊论文
Functional characterization of KlippelTrenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis
Chen, Di1,2; Li, Lei1; Tu, Xin1,2; Yin, Zhan1,3; Wang, Qing1,2,4; Yin, Z (reprint author), Ctr Human Genome Res, 1037 Luoyu Rd, Wuhan, Peoples R China.
2013-03-01
Source PublicationHUMAN MOLECULAR GENETICS
ISSN0964-6906
Volume22Issue:5Pages:963-976
AbstractSpecification 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.; 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.
SubtypeArticle
KeywordKlippel-trenaunay-syndrome Coronary-artery-disease Lymphatic Endothelial-cells Phosphatidylinositol 3-kinase Molecular Characterization Kinase Pathways Transgenic Mice Smooth-muscle Zebrafish Expression
Department[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
DOI10.1093/hmg/dds501
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding OrganizationFundamental 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] ; 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] ; 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] ; 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]
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Genetics & Heredity
WOS SubjectBiochemistry & Molecular Biology ; Genetics & Heredity
WOS IDWOS:000314897600011
WOS KeywordKLIPPEL-TRENAUNAY-SYNDROME ; CORONARY-ARTERY-DISEASE ; LYMPHATIC ENDOTHELIAL-CELLS ; PHOSPHATIDYLINOSITOL 3-KINASE ; MOLECULAR CHARACTERIZATION ; KINASE PATHWAYS ; TRANSGENIC MICE ; SMOOTH-MUSCLE ; ZEBRAFISH ; EXPRESSION
Funding OrganizationFundamental 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] ; 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] ; 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] ; 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]
Citation statistics
Cited Times:38[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ihb.ac.cn/handle/342005/19342
Collection水生生物分子与细胞生物学研究中心_期刊论文
Corresponding AuthorYin, Z (reprint author), Ctr Human Genome Res, 1037 Luoyu Rd, Wuhan, Peoples R China.
Affiliation1.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
Recommended Citation
GB/T 7714
Chen, Di,Li, Lei,Tu, Xin,et al. Functional characterization of KlippelTrenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis[J]. HUMAN MOLECULAR GENETICS,2013,22(5):963-976.
APA Chen, Di,Li, Lei,Tu, Xin,Yin, Zhan,Wang, Qing,&Yin, Z .(2013).Functional characterization of KlippelTrenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis.HUMAN MOLECULAR GENETICS,22(5),963-976.
MLA Chen, Di,et al."Functional characterization of KlippelTrenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis".HUMAN MOLECULAR GENETICS 22.5(2013):963-976.
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