4.8 Article

Arrb2 promotes endothelial progenitor cell-mediated postischemic neovascularization

期刊

THERANOSTICS
卷 10, 期 21, 页码 9899-9912

出版社

IVYSPRING INT PUBL
DOI: 10.7150/thno.45133

关键词

angiogenesis; beta-arrestin 2; endothelial progenitor cells; hind-limb ischemia; neovascularization

资金

  1. National Natural Science Foundation of China [81974219, 81471399]
  2. Science and Technology Commission of Shanghai Municipality-Shanghai Sailing Program [20YF1429000]

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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 beta-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.

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