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  • NAD+ br Role of AR in models of neointima formation Investig

    2023-01-16


    Role of AR in models of neointima formation Investigations into the pathogenesis of lesion formation have often used acute models of mechanical damage to assess the mechanisms regulating the fibro-proliferative response to arterial injury. Models of acute injury used for this purpose include: ligation, placement of a perivascular cuff, or insertion of a catheter/wire (Holt and Tulis, 2013). The remodelling induced by acute arterial injury is not analogous to atherosclerosis but comprises an acute inflammatory response and pronounced VSMC proliferation that may provide insights into the influence of AR-mediated signalling on components of the arterial response to injury. VSMC proliferation may contribute to plaque growth in atherosclerosis but is also important for lesion stabilisation. It is also particularly relevant to conditions such as restenosis following balloon angioplasty/stent placement. Results from initial studies in models of neointimal proliferation were inconsistent (Table 1B), reporting that androgens either had no effect (Chen et al., 1996) or reduced neointimal growth (Hanke et al., 2001, Tharp et al., 2009). Notably, Hanke et al. (2001) used an in vitro model of neointimal proliferation to show a direct inhibition of lesion formation (possibly mediated by AR) by testosterone acting on the arterial wall, whilst the work of Tharp et al. (2009) suggested that the ability of testosterone to limit lesion formation was dependent on the severity of injury. AR was investigated for the first time in a rat model of carotid injury in which DHEA administration reduced neointimal lesion formation (measured by histological staining) but co-administration of an AR antagonist had no effect, suggesting AR-independent mechanisms (Bonnet et al., 2009). More recently, a study from our group demonstrated that androgen/AR actions in neointimal growth are complex and variable (Wu et al., 2014). Castration of wild-type mice increased neointimal lesion size following wire-induced injury but not following ligation of mouse femoral NAD+ in vivo, whereas selective deletion of AR from ECs or VSMCs had no effect on lesion size. This compares with a recent investigation reporting increased neointimal growth following ligation (but not following denuding injury) of the common carotid artery in (male) ARKO mice, compared with controls (Wilhelmson et al., 2016). In vitro investigations using aortic explants suggested this was due to increased VSMC proliferation and migration (which were shown to be inhibited by testosterone in human VSMCs in culture). In our investigation optical projection tomography (Kirkby et al., 2011) and histology were used to measure plaque volume and cross-sectional area. It was demonstrated that castration reduced the volume, but not the cross-sectional area, of wire injury-induced lesions (Wu et al., 2014). This indicates, therefore, the importance of both the method used to induce lesion formation and the techniques used to quantify lesion size. More significantly, perhaps, it also suggests that the influence of AR-mediated signalling on neointimal lesion formation cannot be attributed to AR in the (endothelial or smooth muscle) cells of the arterial wall.
    Roles of AR in vascular remodelling during angiogenesis Since angiogenesis has a role in atherogenesis and inhibitors of angiogenesis can reduce lesion size in atherosclerotic mice (Moulton et al., 1999), it is worth considering the influence of AR-mediated signalling on angiogenesis. Androgen acting through AR-dependent signalling increases proliferation and migration of endothelial progenitor cells in vitro (Foresta et al., 2008), and stimulate vessel growth in an in vivo model of murine hindlimb ischaemia (HLI; Sieveking et al., 2010). Our own use of mice with EC- or VSMC-selective AR deletion in murine HLI suggests a role for AR in VSMC (but not in EC) in regulating limb reperfusion by modulating formation of collateral vessels rather than angiogenesis (Wu et al., 2016). These studies provide further confirmation of AR-mediated regulation of vascular cell biology and may have implications for important processes (lesion angiogenesis/recanalisation, EC regeneration) in atheromatous lesion formation.