Vascular endothelial dysfunction and pharmacological treatment

Figure 1 Mechanisms underlying the reduction in nitric oxide bioavailability involve both reduced nitric oxide production and increased nitric oxide scavenging. A reduction in NO production can be resulted from: (1) decreased L-arginine availability due to L-arginine deficiency and/or changes in L-arginine transporter; (2) accumulation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial NO synthase (eNOS); (3) deficiency or modification of cofactor tetrahydrobiopterin (BH4); (4) altered interactions between eNOS and caveolin due to increased caveolin-1; (5) changes in receptor-coupled G proteins; (6) altered eNOS-heat shock protein 90 (Hsp90) interaction due to changes in Hsp90 abundance; (7) changes in calcium-independent phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)-mediated eNOS activation by tyrosine or serine phosphorylation; and (8) decreased eNOS expression due to reduced eNOS gene transcription and/or decreased eNOS mRNA stability. Increased NO scavenging by reactive oxygen species (ROS) and reactive nitrogen species (RNS) can be due to: (9) eNOS uncoupling related to changes in BH4, caveolin-1 and oxidized low density lipoproteins; (10) increased NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) expression and activity; and (11) increased xanthine oxidase expression and activity. CaM: Calmodulin; DDAH: Dimethylarginine dimethylaminohydrolase; SOD: Superoxide dismutase; NO: Nitric oxide.