3.1 Mechanisms of reduced NO bioavailability in ECs
Patients with HF show an increased vascular tone in both macro- and micro- vessels, mainly because of blunted NO bioavailability (Forstermann et al. , 2017). Physiologically, NO production in ECs is initiated by phosphorylation of eNOS via the PI3K/protein kinase B (Akt) pathway. Hyperglycaemia compromises NO generation by inhibiting the expression of eNOS as well as suppressing the phosphorylation of the active site of eNOS (e.g. Ser1177) (Meza et al. , 2019; Forstermann et al. , 2017). In addition, excessive ROS in ECs consumes NO, which can be prevented by anti-oxidative agents (Mezaet al. , 2019). Next to the above mentioned mechanisms, mechanical forces play a crucial role in modulating NO production within ECs. When exposed to unidirectional high shear stress (12-15 dyne/cm2), the GCX transduces mechanical stimulation to intracellular compartments and triggers diverse downstream pathways like PI3K/Akt/eNOS, thus promoting the release of NO (Chistiakovet al. , 2017). Increased blood glucose levels degrade endothelial GCX of diabetic mice (Zuurbier et al. , 2005), suggesting a potential interaction between hyperglycaemia and GCX in eNOS-dependent NO production.