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.