**3. Agonists**

Significant performance of injurious agonists allow for permissive emergence of dysfunc‐ tional endothelial cells in a mode of participation that includes a shift especially of pheno‐ typic determination of such vascular wall components as smooth muscle cells from the tunica media. Within such a setting, the distributional attributes of a contractile versus se‐ cretory phenotype of smooth muscle cells allows for the expression of injurious agonists that further compromise the recoverability from endothelial cell injury in particular. The func‐ tion of the ubiquitin-proteasome system deviates from the norm in atherogenesis and this may necessitate new UPS-based therapeutic modalities [29]. Indeed, the very identity of the dysfunctional state of overlying endothelial cells may prove a derived parameter of conse‐ quence within systems of active remodelling of the intima as induced by such phenotypic shifts in activity of smooth muscle cells in particular.

Aldose reductase in the polyol pathway promotes excessive accumulation of intracellular re‐ active oxygen species in various tissues of diabetic patients [34].
