title: AIP1 mediates vascular endothelial cell growth factor receptor-3-dependent angiogenic and lymphangiogenic responses.
abstract: OBJECTIVE
  To investigate the novel function of ASK1-interacting protein-1 (AIP1) in vascular endothelial cell growth factor receptor (VEGFR)-3 signaling, and VEGFR-3-dependent angiogenesis and lymphangiogenesis.
  
  
  RESULTS
  AIP1, a signaling scaffold protein, is highly expressed in the vascular endothelium. We have previously reported that AIP1 functions as an endogenous inhibitor in pathological angiogenesis by blocking VEGFR-2 activity. Surprisingly, here we observe that mice with a global deletion of AIP1-knockout mice (AIP1-KO) exhibit reduced retinal angiogenesis with less sprouting and fewer branches. Vascular endothelial cell (but not neuronal)-specific deletion of AIP1 causes similar defects in retinal angiogenesis. The reduced retinal angiogenesis correlates with reduced expression in VEGFR-3 despite increased VEGFR-2 levels in AIP1-KO retinas. Consistent with the reduced expression of VEGFR-3, AIP1-KO show delayed developmental lymphangiogenesis in neonatal skin and mesentery, and mount weaker VEGF-C-induced cornea lymphangiogenesis. In vitro, human lymphatic endothelial cells with AIP1 small interfering RNA knockdown, retinal endothelial cells, and lymphatic endothelial cells isolated from AIP1-KO all show attenuated VEGF-C-induced VEGFR-3 signaling. Mechanistically, we demonstrate that AIP1 via vegfr-3-specific miR-1236 increases VEGFR-3 protein expression and that, by directly binding to VEGFR-3, it enhances VEGFR-3 endocytosis and stability.
  
  
  CONCLUSIONS
  Our in vivo and in vitro results provide the first insight into the mechanism by which AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic signaling.
authors.affiliation: From the Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (H.J.Z., X.C., Q.H., H.Z., Y.W., Y.J., W.M.); State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China (H.J.Z., X.C., X.L., L.L.); Diseases of the Aorta Lab, Center for the Endothelium, Vascular Biology Program, Centenary Institute and University of Sydney, Sydney, Australia (R.L.); Department of Ophthalmology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China (Z.X.).
authors.forename: Huanjiao Jenny
authors.initials: HJ
authors.lastname: Zhou
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Chen
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Huang
authors.forename: Renjing
authors.initials: R
authors.lastname: Liu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Yingdi
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liang
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003315:Cornea; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000502:physiology; D051528:Guanylate Kinases; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051880:Receptors, Notch / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015861:Retinal Neovascularization / Q000503:physiopathology*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C561450:Dab2ip protein, mouse; D005136:Eye Proteins; D035683:MicroRNAs; C587824:Mirn1236 microRNA, mouse; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D011994:Recombinant Proteins; D042582:Vascular Endothelial Growth Factor C; D020703:ras GTPase-Activating Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D051528:Guanylate Kinases; C485777:MAGI2 protein, human
keywords: DAB2IP protein, human; lymphangiogenesis; vascular endothelial growth factor A; vascular endothelial growth factor receptor-2; vascular endothelial growth factor receptor-3