Theranostics 2020; 10(21):9899-9912. doi:10.7150/thno.45133 This issue Cite

Research Paper

Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization

Xuelian Wang1,2*, Gaojian Huang1,2*, Jiaxin Mu*3, Zhilei Cong4, Shuyan Chen2, Dong Fu5✉, Jia Qi1✉, Zhen Li2✉

1. Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Department of Geriatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Department of Cardiology, Shanghai East Hospital of Clinical Medical College, Nanjing Medical University, Nanjing, China.
4. Department of Emergency, Huashan Hospital affiliated to Fudan University, Shanghai, China.
5. Department of General Surgery, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai, China.
*These authors contributed equally to this article.

Citation:
Wang X, Huang G, Mu J, Cong Z, Chen S, Fu D, Qi J, Li Z. Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization. Theranostics 2020; 10(21):9899-9912. doi:10.7150/thno.45133. https://www.thno.org/v10p9899.htm
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Abstract

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Background and aim: Modulating biological functions of endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis in ischemic vascular diseases. This study aimed to explore the role and molecular mechanisms of β-arrestin 2 (Arrb2) in EPCs biology and angiogenic therapy.

Methods: The influence of Arrb2 on postischemic neovascularization was evaluated in Arrb2-deficient mice. The proliferation, apoptosis, and various functions of EPCs were analyzed in vitro by manipulating the expression of Arrb2. Finally, the in vivo effect of Arrb2 on EPC-mediated neovascularization was investigated in a mouse model of hind-limb ischemia (HLI).

Results: Arrb2-deficient mice exhibited impaired blood flow recovery based on laser Doppler measurements and reduced capillary density in the adductor muscle after unilateral HLI. Arrb2-deficient mice also showed restricted intraplug angiogenesis in subcutaneously implanted Matrigel plugs. In vitro, lentivirus-mediated Arrb2 overexpression promoted EPC proliferation, migration, adhesion, and tube formation, whereas Arrb2 knockdown had opposite effects. In addition, the overexpression of Arrb2 in EPCs protected them from hypoxia-induced apoptosis and improved intraplug angiogenesis ex vivo. Mechanistically, Arrb2 interacted with and activated extracellular signal-regulated kinase (ERK)1/2 and protein kinase B (Akt) signaling pathways. Finally, the transplantation of EPCs overexpressing Arrb2 resulted in a significantly higher blood flow restoration in ischemic hind limb and higher capillary density during histological analysis compared with control or Arrb2-knockdown EPC-treated nude mice.

Conclusions: The data indicated that Arrb2 augmented EPC-mediated neovascularization through the activation of ERK and Akt signaling pathways. This novel biological function of Arrb2 might provide a potential therapeutic option to promote EPCs in the treatment of ischemic vascular diseases.

Keywords: angiogenesis, β-arrestin 2, endothelial progenitor cells, hind-limb ischemia, neovascularization


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APA
Wang, X., Huang, G., Mu, J., Cong, Z., Chen, S., Fu, D., Qi, J., Li, Z. (2020). Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization. Theranostics, 10(21), 9899-9912. https://doi.org/10.7150/thno.45133.

ACS
Wang, X.; Huang, G.; Mu, J.; Cong, Z.; Chen, S.; Fu, D.; Qi, J.; Li, Z. Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization. Theranostics 2020, 10 (21), 9899-9912. DOI: 10.7150/thno.45133.

NLM
Wang X, Huang G, Mu J, Cong Z, Chen S, Fu D, Qi J, Li Z. Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization. Theranostics 2020; 10(21):9899-9912. doi:10.7150/thno.45133. https://www.thno.org/v10p9899.htm

CSE
Wang X, Huang G, Mu J, Cong Z, Chen S, Fu D, Qi J, Li Z. 2020. Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization. Theranostics. 10(21):9899-9912.

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