title: CD82 restrains pathological angiogenesis by altering lipid raft clustering and CD44 trafficking in endothelial cells.
abstract: BACKGROUND
  Angiogenesis is crucial for many pathological processes and becomes a therapeutic strategy against diseases ranging from inflammation to cancer. The regulatory mechanism of angiogenesis remains unclear. Although tetraspanin CD82 is widely expressed in various endothelial cells (ECs), its vascular function is unknown.
  
  
  RESULTS
  Angiogenesis was examined in Cd82-null mice with in vivo and ex vivo morphogenesis assays. Cellular functions, molecular interactions, and signaling were analyzed in Cd82-null ECs. Angiogenic responses to various stimuli became markedly increased upon Cd82 ablation. Major changes in Cd82-null ECs were enhanced migration and invasion, likely resulting from the upregulated expression of cell adhesion molecules such as CD44 and integrins at the cell surface and subsequently elevated outside-in signaling. Gangliosides, lipid raft clustering, and CD44-membrane microdomain interactions were increased in the plasma membrane of Cd82-null ECs, leading to less clathrin-independent endocytosis and then more surface presence of CD44.
  
  
  CONCLUSIONS
  Our study reveals that CD82 restrains pathological angiogenesis by inhibiting EC movement, that lipid raft clustering and cell adhesion molecule trafficking modulate angiogenic potential, that transmembrane protein modulates lipid rafts, and that the perturbation of CD82-ganglioside-CD44 signaling attenuates pathological angiogenesis.
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Quan
authors.initials: Q
authors.lastname: Wei
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Mekel M
authors.initials: MM
authors.lastname: Richardson
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Roy
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: William
authors.initials: W
authors.lastname: Rodgers
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Yuechueng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Chenying
authors.initials: C
authors.lastname: Fu
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Lexi
authors.initials: L
authors.lastname: Ding
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Satish
authors.initials: S
authors.lastname: Pasula
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Huang
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Markus
authors.initials: M
authors.lastname: Thali
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.).
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.affiliation: From the West China Hospital, Sichuan University, Chengdu, China (Q.W.); University of Oklahoma Health Science Center, Oklahoma City (Q.W., F.Z., M.M.R., W.R., Y.L., C.F., Y.D., C.H., L.D., Y.H., J.M., X.A.Z.); University of Vermont, Burlington (N.H.R., M.T.); University of Tennessee, Memphis (W.Z., Y.C., Y.S.); Tongji Hospital, Wuhan, China (Y.D., X.H.); Indiana University, Indianapolis (M.E.B.); Oklahoma Medical Research Foundation, Oklahoma City (S.P., J.D.W.); and German Cancer Research Center, Heidelberg, Germany (S.T., G.J.H.). xin-zhang-1@ouhsc.edu.
authors.forename: Xin A
authors.initials: XA
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005732:Gangliosides / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051861:Kangai-1 Protein / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: C476399:Cd44 protein, mouse; C497689:Cd82 antigen, mouse; D015815:Cell Adhesion Molecules; D005732:Gangliosides; D018960:Hyaluronan Receptors; D051861:Kangai-1 Protein
keywords: cell movement; endocytosis; membrane microdomains; neovascularization, pathological