**2.1. Endothelial dysfunction in diabetes**

Dysfunction of vascular endothelium is considered not only as an important factor in the initiation of vascular complications, but also in its progression and clinical sequelae [5]. Endothelial dysfunction is the loss of endothelium physiological properties with a shift toward a vasoconstrictor, prothrombotic, and pro-inflammatory state [2].

The mechanisms underlying the development of endothelial dysfunction in type 2 diabetes are complex and include oxidative stress, inflammation, and chronic alterations in the hemodynamic balance. Several contributors to endothelial activation and dysregulation have been described: decreased tetrahydrobiopterin (BH<sup>4</sup> ) bioavailability and eNOS uncoupling, increased arginase, increased ROS production, decreased NO bioavailability, increased asymmetric dimethyl arginine, increased glycation and expression of receptor for advanced glycation end products (RAGE), nuclear factor κB (NFκB) activation, suppression of Kruppel-like Factor 2 [6], and phenotypic changes in perivascular adipose tissue leading to low grade inflammation and reduced adiponectin secretion [7, 8].
