title: Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin.
abstract: Aggf1 is the first gene identified for Klippel-Trenaunay syndrome (KTS), and encodes an angiogenic factor. However, the in vivo roles of Aggf1 are incompletely defined. Here we demonstrate that Aggf1 is essential for both physiological angiogenesis and pathological tumour angiogenesis in vivo. Two lines of Aggf1 knockout (KO) mice showed a particularly severe phenotype as no homozygous embryos were observed and heterozygous mice also showed embryonic lethality (haploinsufficient lethality) observed only for Vegfa and Dll4. Aggf1+/- KO caused defective angiogenesis in yolk sacs and embryos. Survived adult heterozygous mice exhibit frequent haemorrhages and increased vascular permeability due to increased phosphorylation and reduced membrane localization of VE-cadherin. AGGF1 inhibits VE-cadherin phosphorylation, increases plasma membrane VE-cadherin in ECs and in mice, blocks vascular permeability induced by ischaemia-reperfusion (IR), restores depressed cardiac function and contraction, reduces infarct sizes, cardiac fibrosis and necrosis, haemorrhages, edema, and macrophage density associated with IR. Mechanistically, AGGF1 promotes angiogenesis by activating catalytic p110α subunit and p85α regulatory subunit of PI3K, leading to activation of AKT, GSK3β and p70S6K. AKT activation is significantly reduced in heterozygous KO mice and isolated KO ECs, which can be rescued by exogenous AGGF1. ECs from KO mice show reduced capillary angiogenesis, which is rescued by AGGF1 and AKT. Tumour growth/angiogenesis is reduced in heterozygous mice, which was associated with reduced activation of p110α, p85α and AKT. Together with recent identification of somatic mutations in p110α (encoded by PIK3CA), our data establish a potential mechanistic link between AGGF1 and PIK3CA, the two genes identified for KTS.
authors: The Center for Cardiovascular Genetics, Department of Molecular Cardiology, NE40, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.
authors: Teng
authors: T
authors: Zhang
authors: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors: Yufeng
authors: Y
authors: Yao
authors: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors: Jingjing
authors: J
authors: Wang
authors: Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.
authors: Yong
authors: Y
authors: Li
authors: The Center for Cardiovascular Genetics, Department of Molecular Cardiology, NE40, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.
authors: Ping
authors: P
authors: He
authors: The Center for Cardiovascular Genetics, Department of Molecular Cardiology, NE40, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.
authors: Vinay
authors: V
authors: Pasupuleti
authors: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors: Zhengkun
authors: Z
authors: Hu
authors: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors: Xinzhen
authors: X
authors: Jia
authors: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors: Qixue
authors: Q
authors: Song
authors: The Center for Cardiovascular Genetics, Department of Molecular Cardiology, NE40, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.
authors: Xiao-Li
authors: XL
authors: Tian
authors: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.
authors: Changqing
authors: C
authors: Hu
authors: The Center for Cardiovascular Genetics, Department of Molecular Cardiology, NE40, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.
authors: Qiuyun
authors: Q
authors: Chen
authors: The Center for Cardiovascular Genetics, Department of Molecular Cardiology, NE40, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, OH, USA.|Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China.|Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors: Qing Kenneth
authors: QK
authors: Wang
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D007715:Klippel-Trenaunay-Weber Syndrome / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D000099152:Cadherin 5
chemical_list: D042501:Angiogenic Proteins; D015703:Antigens, CD; D015820:Cadherins; D058534:Class I Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000099152:Cadherin 5; C000619510:Aggf1 protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse