2.1 Increased vascular inflammation in ECs
During hyperglycaemia, binding of AGEs to RAGE elevates adhesion molecule expression, production of cytokines and growth factors via the activation of ERK, JNK, and phosphoinositol 3-kinase (PI3k) pathways. AGEs directly stimulate monocytes to produce inflammatory mediators like interleukins (ILs) and TNF-α, and thereby further enhance local inflammation of the vascular wall (Jin et al. , 2018). Moreover, excessive production of ROS induces vascular inflammation in ECs via upregulating intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) (Daiber et al. , 2020). The oxidative stress triggers cytokine secretion mainly in an “inflammasome-dependent” manner (Bai et al. , 2020). Briefly, ROS activate NF-κB and upregulate the expression level of NOD-like receptor containing pyrin domain 3 (NLRP3) inflammasome as well as pro-IL-1β. Then, NLRP3 inflammasome is activated through assembling of NLRP3, caspase-1 and apoptosis-associated speck-like protein containing a CARD (caspase activation and recruitment domain), forming a complex for the final production of active caspase-1, IL-1β and IL-18. This process is also accelerated by ROS (Ferrucci et al. , 2018; Toldoet al. , 2021). Intriguingly, pro-inflammatory mediators released during inflammation like TNF-α can induce ROS production, thus promoting the “vicious circle” of oxidative stress and inflammation (Yuanet al. , 2019).