Regenerated endothelium and its senescent response to aggregating platelets

Abstract

This essay summarizes 30 years of work attempting to understand why regenerated endothelium becomes dysfunctional. It focuses on the activation of endothelial nitric oxide synthase (eNOS) and the production of NO in response to platelet products and thrombin, which represents a first-line protection against vasospasm and atherosclerosis. Serotonin and adenosine diphosphate released by aggregating platelets are coupled to the activation of eNOS by different G-proteins. The endothelium-dependent relaxation that they cause is modulated non-selectively by the lipid content in the diet. When the endothelium regenerates after mechanical disruption, the newly formed endothelial cells selectively lose their Gi-mediated coupling and become less responsive to serotonin and thrombin. Accelerated senescence and the emergence of adipocyte-fatty acid binding protein leading to increased oxidative stress play a key role in the genesis of the dysfunction of regenerated endothelium. The consequent local NO deficiency not only favors the occurrence of vasospasm but sets the stage for the occurrence of atherosclerosis.