**2. Molecular mechanisms triggered by AGEs in the endothelium**

It is generally accepted that AGEs target cells by three main mechanisms. First, proteins modified by AGEs have altered biological function, either enzymatic activity, binding properties or structural conformation. Second, extracellular matrix components modified by AGEs interact abnormally with other matrix components and with matrix receptors, such as integrins. This includes also the formation of new links or the alteration of those previously existing, between proteins, which may alter the physical properties of extracellular matrix and cell environment. Third, plasma proteins modified by AGEs bind to cell surface receptors, of which the receptor for AGEs (RAGE) is acknowledged to be the most important, activating intracellular signaling pathways and various cellular responses.

Binding of AGEs to RAGE is responsible for the generation of reactive oxygen species (ROS) and the activation of transcription factors such as nuclear factor-κB (NF-κB), with subsequent changes in the expression of many genes involved in vascular inflammation and endothelial dysfunction [18–20]. Besides from the involvement of AGEs-RAGE axis, the precursors of AGEs, like Amadori products or early glycated products also have a role in the global response of non-enzymatic glycation of proteins, so we will also discuss their effects on endothelial cells.
