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The role of integrin αv expressed by VSMCs in vascular fibrosis

Abstract : Arterial stiffness is an independent risk factor for cardiovascular morbidity/mortality. It has been demonstrated that arterial stiffness is linked to arterial fibrosis manifested by increased synthesis of collagen and other extracellular matrix components. Integrins, Transmembrane receptors mediating cell-cell and cell-matrix signaling pathways, are involved in tissue fibrosis. Galectin-3, a novel marker for diagnosis and prognosis of heart failure patients, also plays an important role in fibrosis. However, the molecular mechanisms whereby galectin-3 induces vascular fibrosis are still unclear. We studied the role of integrin αv in Ang II-induced VSMCs arterial fibrosis and stiffness via a SMC specific knock-out of integrin αv mouse model (αv SMKO), induced in adult mice by injection of tamoxifen. We could not find any difference in vascular fibrosis in basal conditions between control and mutant mice. However, decreased arterial fibrosis was observed in αv SMKO mutant mice 28-day after Ang II perfusion. Analysis of RNA from aorta of control and mutant mice by Affymetrix microarrays indicated alteration of TGF-β pathway in Ang II-treated mutant mice. In order to examine the mechanism associated to the decreased fibrosis in VSMCs of αvSMKO mice, we used integrin αv-floxed VSMCs in culture and biochemical methods to analyze the phosphorylation of signaling components and fibrosis-related proteins synthesis following integrin αv inactivation and/or treatment of TGF-β1, Ang-II or galectin-3. Our results indicated that TGF-β1 or Ang-II increased the expression of collagen and fibronectin at the protein level as well as the phosphorylation of ERK and smad2/3 in the control cells, while inactivation of integrin αν partly inhibited the TGF-β1- and Ang-II-induced effects above. Integrin αv was required for Ang II-induced expression of galectin-3 in the VSMCs. Duolink method demonstrated that galectin-3 interacted directly with integrin αv. We also showed that galectin-3 activated AKT, ERK, and Wnt/β-catenin signaling components. The activation of AKT and Wnt/β-catenin signaling pathways, but not ERK signaling pathway, by galectin-3 was inhibited by the knock-down of integrin αv. At cellular level, galectin-3-induced an increase in cell proliferation, migration and synthesis of several fibrosis-related proteins were also significantly inhibited by knock-down of integrin αv. The specific inhibitor of AKT signaling pathway (LY294002) inhibited the activation of downstream Wnt/β-catenin signaling pathway and decreased the response of VSMCs to galectin-3 treatment. Our study indicates a role of integrin αv in the Ang II or TGF-β1 induced arterial fibrogenesis. Galectin-3, interacting with integrin αv, depends on integrin αv/AKT/Wnt/β-catenin signaling pathway to regulate the proliferation, migration and expression of fibrosis-related proteins in VSMCs.
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Lei Tian. The role of integrin αv expressed by VSMCs in vascular fibrosis. Cellular Biology. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS103⟩. ⟨tel-02886136⟩

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