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Lymphangiogenesis contributes to exercise-induced physiological cardiac growth

BACKGROUND: Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart. Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes. However, it remains unclear whether and how lymphangiogenesis contributes to...

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Autores principales: Bei, Yihua, Huang, Zhenzhen, Feng, Xing, Li, Lin, Wei, Meng, Zhu, Yujiao, Liu, Shuqin, Chen, Chen, Yin, Mingming, Jiang, Huimin, Xiao, Junjie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Shanghai University of Sport 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338339/
https://www.ncbi.nlm.nih.gov/pubmed/35218948
http://dx.doi.org/10.1016/j.jshs.2022.02.005
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author Bei, Yihua
Huang, Zhenzhen
Feng, Xing
Li, Lin
Wei, Meng
Zhu, Yujiao
Liu, Shuqin
Chen, Chen
Yin, Mingming
Jiang, Huimin
Xiao, Junjie
author_facet Bei, Yihua
Huang, Zhenzhen
Feng, Xing
Li, Lin
Wei, Meng
Zhu, Yujiao
Liu, Shuqin
Chen, Chen
Yin, Mingming
Jiang, Huimin
Xiao, Junjie
author_sort Bei, Yihua
collection PubMed
description BACKGROUND: Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart. Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes. However, it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth. We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth. METHODS: Adult C57BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth. Oral treatment with vascular endothelial growth factor receptor 3 (VEGFR3) inhibitor SAR131675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation. Furthermore, human dermal lymphatic endothelial cell (LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy. RESULTS: Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1–positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels. VEGFR3 was upregulated in the exercised heart, while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes, which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise. Furthermore, LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulin-like growth factor-1 and the extracellular protein Reelin, while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects. Functional rescue assays further demonstrated that protein kinase B (AKT) activation, as well as reduced CCAAT enhancer-binding protein beta (C/EBPβ) and increased CBP/p300-interacting transactivators with E (glutamic acid)/D (aspartic acid)–rich-carboxylterminal domain 4 (CITED4), contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation. CONCLUSION: Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation, and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis. These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.
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spelling pubmed-93383392022-08-01 Lymphangiogenesis contributes to exercise-induced physiological cardiac growth Bei, Yihua Huang, Zhenzhen Feng, Xing Li, Lin Wei, Meng Zhu, Yujiao Liu, Shuqin Chen, Chen Yin, Mingming Jiang, Huimin Xiao, Junjie J Sport Health Sci Original Article BACKGROUND: Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart. Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes. However, it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth. We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth. METHODS: Adult C57BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth. Oral treatment with vascular endothelial growth factor receptor 3 (VEGFR3) inhibitor SAR131675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation. Furthermore, human dermal lymphatic endothelial cell (LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy. RESULTS: Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1–positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels. VEGFR3 was upregulated in the exercised heart, while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes, which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise. Furthermore, LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulin-like growth factor-1 and the extracellular protein Reelin, while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects. Functional rescue assays further demonstrated that protein kinase B (AKT) activation, as well as reduced CCAAT enhancer-binding protein beta (C/EBPβ) and increased CBP/p300-interacting transactivators with E (glutamic acid)/D (aspartic acid)–rich-carboxylterminal domain 4 (CITED4), contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation. CONCLUSION: Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation, and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis. These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth. Shanghai University of Sport 2022-07 2022-02-23 /pmc/articles/PMC9338339/ /pubmed/35218948 http://dx.doi.org/10.1016/j.jshs.2022.02.005 Text en © 2022 Published by Elsevier B.V. on behalf of Shanghai University of Sport. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Bei, Yihua
Huang, Zhenzhen
Feng, Xing
Li, Lin
Wei, Meng
Zhu, Yujiao
Liu, Shuqin
Chen, Chen
Yin, Mingming
Jiang, Huimin
Xiao, Junjie
Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
title Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
title_full Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
title_fullStr Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
title_full_unstemmed Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
title_short Lymphangiogenesis contributes to exercise-induced physiological cardiac growth
title_sort lymphangiogenesis contributes to exercise-induced physiological cardiac growth
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338339/
https://www.ncbi.nlm.nih.gov/pubmed/35218948
http://dx.doi.org/10.1016/j.jshs.2022.02.005
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