TLR4 and aneurysm: In conjunction with current knowledge obtained from previous studies [12,20,33], it appears reasonable that both TLR4, mainly on VSMCs, and RAGE, mainly on macrophages, transduce the proinflammatory activity of DAMPs such as HMGB1 to perpetuate inflammatory responses and proteolytic degradation during aneurysm development (Fig 6), as observed in other chronic inflammatory conditions [3,7,8].