title: Nucleoside diphosphate kinase B regulates angiogenesis through modulation of vascular endothelial growth factor receptor type 2 and endothelial adherens junction proteins.
abstract: OBJECTIVE
  Nucleoside diphosphate kinase B (NDPKB) participates in the activation of heterotrimeric and monomeric G proteins, which are pivotal mediators in angiogenic signaling. The role of NDPKB in angiogenesis has to date not been defined. Therefore, we analyzed the contribution of NDPKB to angiogenesis and its underlying mechanisms in well-characterized in vivo and in vitro models.
  
  
  RESULTS
  Zebrafish embryos were depleted of NDPKB by morpholino-mediated knockdown. These larvae displayed severe malformations specifically in vessels formed by angiogenesis. NDPKB-deficient (NDPKB(-/-)) mice were subjected to oxygen-induced retinopathy. In this model, the number of preretinal neovascularizations in NDPKB(-/-) mice was strongly reduced in comparison with wild-type littermates. In accordance, a delayed blood flow recovery was detected in the NDPKB(-/-) mice after hindlimb ligation. In in vitro studies, a small interfering RNA-mediated knockdown of NDPKB was performed in human umbilical endothelial cells. NDPKB depletion impaired vascular endothelial growth factor (VEGF)-induced sprouting and hampered the VEGF-induced spatial redistributions of the VEGF receptor type 2 and VE-cadherin at the plasma membrane. Concomitantly, NDPKB depletion increased the permeability of the human umbilical endothelial cell monolayer.
  
  
  CONCLUSIONS
  This is the first report to show that NDPKB is required for VEGF-induced angiogenesis and contributes to the correct localization of VEGF receptor type 2 and VE-cadherin at the endothelial adherens junctions. Therefore, our data identify NDPKB as a novel molecular target to modulate VEGF-dependent angiogenesis.
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Shalini
authors.initials: S
authors.lastname: Gross
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Wolf
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Vicki M
authors.initials: VM
authors.lastname: Butenschön
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Kavi
authors.initials: K
authors.lastname: Devraj
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebner
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.).
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.affiliation: From the Institute of Experimental and Clinical Pharmacology and Toxicology (Y.F., S.G., N.M.W., V.M.B., Y.Q., T.W.), Department of Vascular Biology and Tumor Angiogenesis (J.K.), and the Fifth Medical Clinic (H.-P.H.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute of Neurology (Edinger-Institute), Goethe University, Frankfurt, Germany (K.D., S.L.); and Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.). thomas.wieland@medma.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D007511:Ischemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D020127:Recovery of Function; D012039:Regional Blood Flow; D015861:Retinal Neovascularization / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D054778:NM23 Nucleoside Diphosphate Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D029961:Zebrafish Proteins; D000099152:Cadherin 5; C000588866:KDR protein, human; C517940:NME2 protein, human; C517941:Nme2 protein, mouse
keywords: NDPKB; Nme2; VEGFR2; angiogenesis; endothelial permeability; nucleoside diphosphate kinase