Figure 3.

Initiators of endothelial (vascular) dysfunction. Aging, inflammation, mental stress and oxidative stress are strong triggers of endothelial (vascular) dysfunction. It should be noted that to a certain extent the classical risk factors (see top of the scheme) converge at the level of inflammation and oxidative stress to further trigger the down‐stream pathomechanisms. Inflammation can have detrimental effects by direct effects of cytokines on vascular cells leading to activation of secondary sources of ROS, direct leukocyte‐derived ROS formation or effects of infiltrated immune cells on vascular structure and function. Aging and mental stress act via oxidative stress, inflammation but can also directly affect the major triggers of endothelial (vascular) dysfunction such as are eNOS uncoupling, sGC oxidation (maybe also imbalanced phosphodiesterase expression/activity), prostacyclin synthase (PGIS) nitration and inactivation, redox‐triggered endothelin‐1 (ET‐1) signalling, activation of the renin‐angiotensin‐aldosterone system (RAAS) and other stress hormones (catecholamines), and finally, AGE/RAGE signalling. In addition, dysregulated arginase metabolism decreases levels of the eNOS substrate L‐arginine. The quality of high density lipoprotein (HDL) changes under oxidative stress conditions and metabolic disease. Other factors that also contribute to endothelial (vascular) dysfunction are changes in fatty acid metabolism and release of adipokines by perivascular adipose tissue (PVAT) that occurs in some diseases.