title: Interferon-induced transmembrane protein 1 regulates endothelial lumen formation during angiogenesis.
abstract: OBJECTIVE
  It is well established that angiogenesis is a complex and coordinated multistep process. However, there remains a lack of information about the genes that regulate individual stages of vessel formation. Here, we aimed to define the role of human interferon-induced transmembrane protein 1 (IFITM1) during blood vessel formation.
  
  
  RESULTS
  We identified IFITM1 in a microarray screen for genes differentially regulated by endothelial cells (ECs) during an in vitro angiogenesis assay and found that IFITM1 expression was strongly induced as ECs sprouted and formed lumens. We showed by immunohistochemistry that human IFITM1 was expressed by stable blood vessels in multiple organs. siRNA-mediated knockdown of IFITM1 expression spared EC sprouting but completely disrupted lumen formation, in both in vitro and in an in vivo xeno-transplant model. ECs lacking IFITM1 underwent early stages of lumenogenesis (ie, intracellular vacuole formation) but failed to mature or expand lumens. Coimmunoprecipitation studies confirmed occludin as an IFITM1 binding partner in ECs, and immunocytochemistry showed a lack of occludin at endothelial tight junctions in the absence of IFITM1. Finally, time-lapse video microscopy revealed that IFITM1 is required for the formation of stable cell-cell contacts during endothelial lumen formation.
  
  
  CONCLUSIONS
  IFITM1 is essential for the formation of functional blood vessels and stabilizes EC-EC interactions during endothelial lumen formation by regulating tight junction assembly.
authors.affiliation: From the Department of Molecular Biology and Biochemistry (S.A.P., M.E.Z., M.T.H., C.I.S., A.H.F., K.M.W.-R., J.P., C.C.W.H.), Department of Biomedical Engineering (X.C., C.C.W.H.), Edwards Lifesciences Center for Advanced Cardiovascular Technology (C.C.W.H.), and Chao Family Comprehensive Cancer Center (C.C.W.H.), University of California Irvine.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Popson
authors.forename: Mary E
authors.initials: ME
authors.lastname: Ziegler
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Chen
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Holderfield
authors.forename: Cameron I
authors.initials: CI
authors.lastname: Shaaban
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Fong
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Welch-Reardon
authors.forename: Jackie
authors.initials: J
authors.lastname: Papkoff
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D018715:Microscopy, Video; D018919:Neovascularization, Physiologic; D062793:Occludin / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D013997:Time Factors; D059008:Time-Lapse Imaging; D014162:Transfection
chemical_list: D000943:Antigens, Differentiation; C568985:OCLN protein, human; D062793:Occludin; C062010:leu-13 antigen
keywords: angiogenesis modulators; blood vessels; endothelial cells; intercellular junctions