Changyue Xue1, Jiamin Xie2, Dan Zhao1, Shiyu Lin1, Tengfei Zhou1, Sirong Shi1, Xiaoru Shao1, Yunfeng Lin1, Bofeng Zhu3,4, Xiaoxiao Cai1. 1. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. 2. Department of Stomatology, Shanghai Pudong Hospital, Shanghai, China. 3. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shanxi, China. 4. Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shanxi, China.
Abstract
OBJECTIVES: The aim of the study was to investigate the role of the JAK/STAT3 signalling pathway in angiogenesis. MATERIALS AND METHODS: The model established in vitro, involved a 3D collagen gel being implanted with endothelial cells (ECs) from red fluorescent protein-labelled mice, and adipose-derived stromal cells (ASCs) from green fluorescent protein-labelled mice. Phenomena of angiogenesis, after treatment by the inhibitor and the activator of JAK/STAT3 pathway respectively, were observed using confocal laser scanning microscopy. Transwell co-culture of ECs and ASCs was used to elucidate mechanisms. RESULTS: Stattic, inhibitor of JAK/STAT3 pathway, attenuated angiogenesis in the model. In contrast, angiogenesis was promoted after treatment of Olanzapine, an activator. We found that protein levels of VEGFA and cyclin D1 were regulated by the JAK/STAT3 pathway, and flow cytometry further confirmed variations in cell cycle parameters of ECs and ASCs. Genes VEGFA/B, VEGFR2, MMP-2, MMP-9, IGF-1 and b-FGF were down-regulated by Stattic in ECs, while Olanzapine significantly up-regulated mRNA levels of these genes. As for ASCs, genes VEGFA, MMP-2, MMP-9, IGF-1 and b-FGF were modulated by the JAK/STAT3 pathway. CONCLUSIONS: Angiogenesis in the 3D collagen gel was regulated by the JAK/STAT3 pathway which involved changes in vessel length, vessel diameter and sprout number. The underlying mechanism was that the JAK/STAT3 signalling pathway regulated angiogenesis by modulation of numbers of angiogenesis-related growth factors and by direct regulation of cell cycle.
OBJECTIVES: The aim of the study was to investigate the role of the JAK/STAT3 signalling pathway in angiogenesis. MATERIALS AND METHODS: The model established in vitro, involved a 3D collagen gel being implanted with endothelial cells (ECs) from red fluorescent protein-labelled mice, and adipose-derived stromal cells (ASCs) from green fluorescent protein-labelled mice. Phenomena of angiogenesis, after treatment by the inhibitor and the activator of JAK/STAT3 pathway respectively, were observed using confocal laser scanning microscopy. Transwell co-culture of ECs and ASCs was used to elucidate mechanisms. RESULTS: Stattic, inhibitor of JAK/STAT3 pathway, attenuated angiogenesis in the model. In contrast, angiogenesis was promoted after treatment of Olanzapine, an activator. We found that protein levels of VEGFA and cyclin D1 were regulated by the JAK/STAT3 pathway, and flow cytometry further confirmed variations in cell cycle parameters of ECs and ASCs. Genes VEGFA/B, VEGFR2, MMP-2, MMP-9, IGF-1 and b-FGF were down-regulated by Stattic in ECs, while Olanzapine significantly up-regulated mRNA levels of these genes. As for ASCs, genes VEGFA, MMP-2, MMP-9, IGF-1 and b-FGF were modulated by the JAK/STAT3 pathway. CONCLUSIONS: Angiogenesis in the 3D collagen gel was regulated by the JAK/STAT3 pathway which involved changes in vessel length, vessel diameter and sprout number. The underlying mechanism was that the JAK/STAT3 signalling pathway regulated angiogenesis by modulation of numbers of angiogenesis-related growth factors and by direct regulation of cell cycle.
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