Quan Wei1, Feng Zhang1, Mekel M Richardson1, Nathan H Roy1, William Rodgers1, Yuechueng Liu1, Wenyuan Zhao1, Chenying Fu1, Yingjun Ding1, Chao Huang1, Yuanjian Chen1, Yao Sun1, Lexi Ding1, Yang Hu1, Jian-Xing Ma1, Michael E Boulton1, Satish Pasula1, Jonathan D Wren1, Satoshi Tanaka1, Xiaolin Huang1, Markus Thali1, Günter J Hämmerling1, Xin A Zhang2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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.
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