Int J Med Sci 2022; 19(7):1205-1215. doi:10.7150/ijms.71912 This issue Cite

Research Paper

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43

Zhang-Jian Yang1*, Qiu-Chen Bi1*, Li-Jun Gan1, Le-Ling Zhang1, Min-Jun Wei2, Tao Hong2, Rong Liu1, Cheng-Lin Qiu1, Xiao-Jian Han3,4✉, Li-Ping Jiang1✉

1. Jiangxi Provincial Key Laboratory of Drug Targets and Drug Screening, School of Pharmaceutical Science, Nanchang University, Nanchang 330006, China.
2. Department of Neurosurgery, First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
3. Institute of Geriatrics, Jiangxi provincial People's Hospital, First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China.
4. Department of Neurology, Jiangxi provincial People's Hospital, First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China.
*These authors contributed equally to this work.

Citation:
Yang ZJ, Bi QC, Gan LJ, Zhang LL, Wei MJ, Hong T, Liu R, Qiu CL, Han XJ, Jiang LP. Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43. Int J Med Sci 2022; 19(7):1205-1215. doi:10.7150/ijms.71912. https://www.medsci.org/v19p1205.htm
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Abstract

Graphic abstract

Glioblastoma multiform (GBM) is a highly aggressive primary brain tumor. Exosomes derived from glioma cells under a hypoxic microenvironment play an important role in tumor biology including metastasis, angiogenesis and chemoresistance. However, the underlying mechanisms remain to be elucidated. In this study, we aimed to explore the role of connexin 43 on exosomal uptake and angiogenesis in glioma under hypoxia. U251 cells were exposed to 3% oxygen to achieve hypoxia, and the expression levels of HIF-1α and Cx43, involved in the colony formation and proliferation of cells were assessed. Exosomes were isolated by differential velocity centrifugation from U251 cells under normoxia and hypoxia (Nor-Exos and Hypo-Exos), respectively. Immunofluorescence staining, along with assays for CCK-8, tube formation and wound healing along with a transwell assay were conducted to profile exosomal uptake, proliferation, tube formation, migration and invasion of HUVECs, respectively. Our results revealed that Hypoxia significantly up-regulated the expression of HIF-1α in U251 cells as well as promoting proliferation and colony number. Hypoxia also increased the level of Cx43 in U251 cells and in the exosomes secreted. The uptake of Dio-stained Hypo-Exos by HUVECs was greater than that of Nor-Exos, and inhibition of Cx43 by 37,43gap27 or lenti-Cx43-shRNA efficiently prevented the uptake of Hypo-Exos by recipient endothelial cells. In addition, the proliferation and total loops of HUVECs were remarkably increased at 24 h, 48 h, and 10 h after Hypo-Exos, respectively. Notably, 37,43gap27, a specific Cx-mimetic peptide blocker of Cx37 and Cx43, efficiently alleviated Hypo-Exos-induced proliferation and tube formation by HUVECs. Finally, 37,43gap27 also significantly attenuated Hypo-Exos-induced migration and invasion of HUVECs. These findings demonstrate that exosomal Cx43 contributes to glioma angiogenesis mediated by Hypo-Exos, and suggests that exosomal Cx43 might serve as a potential therapeutic target for glioblastoma.

Keywords: exosome, connexin 43, angiogenesis, hypoxia, glioma


Citation styles

APA
Yang, Z.J., Bi, Q.C., Gan, L.J., Zhang, L.L., Wei, M.J., Hong, T., Liu, R., Qiu, C.L., Han, X.J., Jiang, L.P. (2022). Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43. International Journal of Medical Sciences, 19(7), 1205-1215. https://doi.org/10.7150/ijms.71912.

ACS
Yang, Z.J.; Bi, Q.C.; Gan, L.J.; Zhang, L.L.; Wei, M.J.; Hong, T.; Liu, R.; Qiu, C.L.; Han, X.J.; Jiang, L.P. Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43. Int. J. Med. Sci. 2022, 19 (7), 1205-1215. DOI: 10.7150/ijms.71912.

NLM
Yang ZJ, Bi QC, Gan LJ, Zhang LL, Wei MJ, Hong T, Liu R, Qiu CL, Han XJ, Jiang LP. Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43. Int J Med Sci 2022; 19(7):1205-1215. doi:10.7150/ijms.71912. https://www.medsci.org/v19p1205.htm

CSE
Yang ZJ, Bi QC, Gan LJ, Zhang LL, Wei MJ, Hong T, Liu R, Qiu CL, Han XJ, Jiang LP. 2022. Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43. Int J Med Sci. 19(7):1205-1215.

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