Cellular signaling and NO production

Signaling and Cell Physiology

Abstract

The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor is nitric oxide (NO), which is synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelium-dependent relaxations involve both pertussis-toxin-sensitive Gi (e.g., responses to serotonin, sphingosine 1-phosphate, alpha2-adrenergic agonists, and thrombin) and pertussis-toxin-insensitive Gq (e.g., adenosine diphosphate and bradykinin) coupling proteins. eNOS undergoes a complex pattern of intracellular regulation, including post-translational modifications involving enzyme acylation and phosphorylation. eNOS is reversibly targeted to signal-transducing plasmalemmal caveolae where the enzyme interacts with a number of regulatory proteins, many of which are modified in cardiovascular disease states. The release of nitric oxide by the endothelial cell can be up- (e.g., by estrogens, exercise, and dietary factors) and down-regulated (e.g. oxidative stress, smoking, and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g., diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis-toxin-sensitive pathway for NO release which favors vasospasm, thrombosis, penetration of macrophages, cellular growth, and the inflammatory reaction leading to atherosclerosis. The unraveling of the complex interaction of the pathways regulating the presence and the activity of eNOS will enhance the understanding of the perturbations in endothelium-dependent signaling that are seen in cardiovascular disease states, and may lead to the identification of novel targets for therapeutic intervention.

Keywords

Diabetes G-proteins Hypertension Nitric oxide Nitric oxide synthase Caveola Endothelium-derived relaxing factor (EDRF) Phosphorylation 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Cardiovascular Division, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina

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