Regeneration of the endothelium in vascular injury.
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). The endothelial cells also release substances (endothelium-derived hyperpolarizing factor, EDHF) that cause hyperpolarization of the cell membrane of the underlying vascular smooth muscle. The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive G(i) (alpha(2)-adrenergic activation, serotonin, thrombin) and insensitive G(q) (adenosine diphosphate, bradykinin) coupling proteins. The ability of the endothelial cell to release relaxing factors can be upregulated by impregnation with estrogens, exercise and antioxidants, and down-regulated by oxidative stress and increased presence of oxidized LDL. 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.
Vanhoutte
Paul M
PM
Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21, Sassoon Road, Hong Kong, People's Republic of China. vanhoutt@hku.hk
D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology; D001685:Biological Factors / Q000502:physiology; D001808:Blood Vessels / Q000502:physiology / Q000503:physiopathology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D045462:Endothelium-Dependent Relaxing Factors / Q000502:physiology*; D050556:Fatty Acid-Binding Proteins / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology; D020783:Matrix Metalloproteinase 7 / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology*; D058451:Oxidative Coupling; D018384:Oxidative Stress / Q000502:physiology; D012038:Regeneration; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation; D014664:Vasodilation / Q000502:physiology
D001685:Biological Factors; D045462:Endothelium-Dependent Relaxing Factors; D050556:Fatty Acid-Binding Proteins; D008077:Lipoproteins, LDL; C067410:endothelium-dependent hyperpolarization factor; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; D020783:Matrix Metalloproteinase 7