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  • Title: Glycation of fibronectin impairs angiopoietin-1/Tie-2 signaling through uncoupling Tie-2-α5β1 integrin crosstalk.
    Author: Chen T, Zhou H, Yuan S, Deng X, Li Y, Chen N, You J, Li R, Li T, Zheng Y, Luo M, Lv H, Wu J, Wang L.
    Journal: Cell Signal; 2023 Dec; 112():110916. PubMed ID: 37806542.
    Abstract:
    The dysfunction of angiopoietin-1 (Ang-1)/Tie-2 signaling pathways has been implicated in diabetic complications. However, the underlying molecular mechanisms remain unclear. Fibronectin (FN) is thought to have an important role in regulating Ang-1/Tie-2 signaling activation. But no previous study has investigated the effects of FN glycation on Ang-1/Tie-2 signaling. In the present study, FN was glycated by methylglyoxal (MGO) to investigate whether the glycation of FN contributes to diabetes-induced Ang-1/Tie-2 signaling impairment and to understand the molecular mechanisms involved. The results demonstrated that MGO-glycated FN significantly impaired Ang-1-evoked phosphorylation of Tie-2 and Akt, Ang-1-induced endothelial cell migration and tube formation and Ang-1-mediated cell survival. The glycation of FN also inhibited the binding of α5β1 integrin to Tie-2. Moreover, FN was remarkably modified by AGEs in aortae derived from db/db mice, indicating the glycation of FN in vivo. Ang-1-induced aortic ring vessel outgrowth and Ang-1-mediated cell survival were also both significantly inhibited in aortae from db/db mice compared to that from the wild type littermates. Moreover, FN, rather than glycated FN partly restored aortic ring angiogenesis in db/db mice, indicating that the angiogenesis defect in the db/db mice are due to FN glycation. Collectively, the results in the present study suggest that the glycation of FN impairs Ang-1/Tie-2 signaling pathway by uncoupling Tie-2-α5β1 integrin crosstalk. This may provide a mechanism for Ang-1/Tie-2 signaling dysfunction and angiogenesis failure in diabetic ischaemic diseases.
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