Impaired tumor angiogenesis and VEG-Finduced pathway in endothelial CD146 knockout mice |
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Authors: | Qiqun Zeng Zhenzhen Wu Hongxia Duan Xuan Jiang Tao Tu Di Lu Yongting Luo Ping Wang Lina Song Jing Feng Dongling Yang Xiyun Yan |
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Affiliation: | 1. 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, China2. University of Chinese Academy of Sciences, Beijing 100049, China3. Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd. South, San Francisco, CA 94158, USA |
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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 (CD146EC-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 CD146EC-KO mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatmentwas impairedinendothelial cells (ECs) of CD146EC-KO mice. Mechanistic studies further confirmed that VEGFinduced VEGFR-2 phosphorylation and AKT/p38 MAPKs/ NF-κB activation were inhibited in these CD146-null ECs, whichmight present theunderlyingcause for theobserved inhibition of tumor angiogenesis in CD146EC-KO mice. These results suggest thatCD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis. |
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Keywords: | CD146 tumor angiogenesis VEGF knockout mice |
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