title: Impaired tumor angiogenesis and VEGF-induced pathway in endothelial CD146 knockout mice.
abstract: CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146(EC-KO)) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146(EC-KO) mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) of CD146(EC-KO) mice. Mechanistic studies further confirmed that VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-κB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146(EC-KO) mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Qiqun
authors.initials: Q
authors.lastname: Zeng
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wu
authors.forename: Hongxia
authors.initials: H
authors.lastname: Duan
authors.forename: Xuan
authors.initials: X
authors.lastname: Jiang
authors.forename: Tao
authors.initials: T
authors.lastname: Tu
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.forename: Yongting
authors.initials: Y
authors.lastname: Luo
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Lina
authors.initials: L
authors.lastname: Song
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.forename: Dongling
authors.initials: D
authors.lastname: Yang
authors.forename: Xiyun
authors.initials: X
authors.lastname: Yan
mesh_terms: D000818:Animals; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012169:Retinal Vein / Q000254:growth & development / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051929:CD146 Antigen; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt
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