The 50-Years IUPHAR Anniversary Lecture: Regenerate to be old

Abstract

The endothelium mediates relaxations (dilatations) of the underlying vascular smooth muscle cells. The endothelium-dependent relaxations are due to the release of non-prostanoid vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which is formed from l-arginine by the constitutive endothelial NO synthase (eNOS). NO diffuses to the underlying vascular smooth muscle and stimulates soluble guanylyl cyclase with the resulting production of cyclic GMP. The release of NO from the endothelium can be mediated by both pertussis toxin-sensitive Gi- (e.g. α2-adrenergic agonists, serotonin) and insensitive Gq- (adenosine diphosphate, bradykinin) proteins. The ability of the endothelial cell to release relaxing factors can be upregulated by estrogens, exercise, diet (ω3-unsaturated fatty acids, polyphenols) and antioxidants, and down-regulated by oxidative stress and increased presence of oxidized low density lipoproteins (LDL). It is reduced chronically by aging, smoking, environmental pollution and in hypertension and diabetes. Following injury or apoptotic death, the endothelium regenerates. However, in regenerated endothelial cells, there is an early selective loss of the pertussis-toxin sensitive mechanisms of EDRF-release. Functional studies suggest that abnormal handling of LDL because of increased oxidative stress play a key role in this selective loss. Genomic analysis demonstrates the emergence of fatty acid binding protein-A (A-FBP) and metalloproteinase-7 (MMP7) in regenerated endothelial cells. The reduced release of NO resulting from the endothelial dysfunction in regenerated areas creates a locus minoris resistentiae which favors the occurrence of vasospasm and thrombosis as well as the initiation of atherosclerosis.