title: Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII.
abstract: Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion ofTekeither ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Man
authors.initials: M
authors.lastname: Chu
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Taotao
authors.initials: T
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, Nanjing, China.
authors.forename: Fei
authors.identifier: http://orcid.org/0000-0003-1857-8831
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Ma
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Haijuan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Cam-Su Genomic Resources Center, Soochow University, Suzhou, China.
authors.forename: Pancheng
authors.initials: P
authors.lastname: Xie
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China.
authors.forename: Ningzheng
authors.initials: N
authors.lastname: Dong
authors.affiliation: Cam-Su Genomic Resources Center, Soochow University, Suzhou, China.
authors.forename: Ying
authors.identifier: http://orcid.org/0000-0002-6689-7768
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: The First Affiliated Hospital, Soochow University, Suzhou, China.
authors.forename: Peirong
authors.initials: P
authors.lastname: Lu
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Jincai
authors.initials: J
authors.lastname: Luo
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Center of Excellence, Biomedicum Helsinki University of Helsinki, Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Center for Vascular Research, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Faculty of Medicine, University of Münster, Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|Cam-Su Genomic Resources Center, Soochow University, Suzhou, China.|Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Yulong
authors.identifier: http://orcid.org/0000-0002-0099-3749
authors.initials: Y
authors.lastname: He
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology*; D017353:Gene Deletion; D018390:Gene Targeting; D008643:Mesentery / Q000033:anatomy & histology / Q000196:embryology; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000033:anatomy & histology; D012867:Skin / Q000033:anatomy & histology / Q000196:embryology; D014680:Veins / Q000196:embryology / Q000254:growth & development*
chemical_list: D051837:COUP Transcription Factor II; C497587:Nr2f2 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: COUP-TFII; Tie2; developmental biology; mouse; stem cells; vein specification